Anatomic and physiologic heterogeneity in patients with syndrome X: an intravascular ultrasound study.

OBJECTIVES: We used intravascular ultrasound imaging of the epicardial vessels to assess coronary morphology, vasomotor response to exercise and exercise-vasomotion after beta-adrenoceptor blockade in patients with syndrome X. BACKGROUND: Syndrome X is defined as chest pain, abnormal exercise test results and normal coronary angiographic findings. Because of the limitations of coronary angiography, intravascular ultrasound was used to define coronary pathophysiology. METHODS: Thirty patients with syndrome X were studied with intravascular ultrasound imaging (30 MHz, 4.3F catheter) of all three major epicardial vessels. Supine arm exercise was performed during coronary imaging. Lumen area was assessed at rest and during peak exercise. The exercise-imaging protocol was repeated after loading with 0.1 mg/kg body weight of intravenous propranolol. RESULTS: Three morphologic groups were identified using intravascular ultrasound: normal coronary arteries (no plaque, intimal thickness < 0.25 mm, n = 12), atheromatous disease (mean [+/- SD] area stenosis 37.9 +/- 7.2%, n = 10) and marked intimal thickening (0.73 +/- 0.11 mm, n = 8). Patients with normal coronary arteries displayed a vasodilatory response to exercise (+16.9% area increase); patients with abnormal coronary arteries displayed a vasoconstrictive response to exercise (-17.4% in the group with plaque; -17.6% in the group with intimal thickening). Propranolol loading attenuated the vasodilatory response in the group with normal coronary arteries (+6.4% area increase) and attenuated the vasoconstrictive response in the two groups with abnormal coronary arteries (-8.0% in the group with plaque; -8.8% in the group with intimal thickening). CONCLUSIONS: Most patients with syndrome X have abnormal coronary arteries by intravascular ultrasound. Intravascular ultrasound identifies three distinct morphologic groups: normal coronary arteries, atheromatous plaque and intimal thickening. Exercise-vasomotion is normal in patients with syndrome X who have normal coronary arteries by ultrasound; patients with abnormal arteries (plaque or intimal thickening) have an abnormal (constrictive) response to exercise. Propranolol loading attenuates vasoreactivity in all subgroups, suggesting divergent therapeutic utility.

Recovery of initial body weight and composition after long-term massive overfeeding in men.

To verify the existence of a set point for body mass, the spontaneous evolution of body weight and composition after massive overfeeding was observed in nine lean young Cameroonian (Massa) men participating in a 4-6 mo traditional fattening session (Guru). Anthropometry (skinfold thicknesses) was used to estimate body composition. Peak weight and fat gains were found to be 19 +/- 3.2 (mean +/- SD) kg and 11.8 +/- 2.5 kg, respectively. Two and one-half years after cessation of fattening and a return to daily life and food habits, there was a spontaneous return to initial body weight and body composition of the overfed subjects. Because the subjects were not under social or other stimuli to lose weight, this finding argues in favor of the existence of a biological control of energy balance at a "preferred" level in nonobese individuals.

Effects of cycles of food restriction followed by ad libitum refeeding on body composition and energy expenditure in obese rats.

Male Wistar rats rendered obese by a cafeteria diet were subjected to three successive cycles alternating food restriction with ad libitum cafeteria-diet feeding (WC rats). Body composition, energy intake, energy required for maintenance, and oxygen consumption were studied. Results were compared with those for rats fed a standard stock diet (CON rats) or a cafeteria diet (CAF rats). The rate of weight loss or regain was independent of the number of cycles. WC rats were fatter than CON rats and as fat as CAF rats after the third cycle. Cost of maintenance of WC rats decreased; their oxygen consumption decreased in the lean state, increased again in the fat state, but remained lower than that of CON and CAF rats. We conclude that the practice of successive restriction and refeeding did not result in resistance to weight loss, but rather in a defect in the utilization of energy intake, facilitating the development of obesity.

Obesity and iron status in menstruating women.

The relationship between iron stores and obesity in menstruating women was studied in 20 obese and 20 nonobese women matched for age and contraception. Although no difference was observed in serum iron or total-iron-binding capacity, the obese group showed significantly higher hemoglobin (137 +/- 9 vs 10 g/L, mean +/- SD; P less than 0.01), hematocrit (0.41 +/- 0.02 vs 0.39 +/- 0.03, P less than 0.05), and serum ferritin concentrations (48.0 +/- 44.3 vs 25.8 +/- 19.5 micrograms/L, P less than 0.05). There was no difference between obese and nonobese women in either the menstrual-cycle interval or the duration of the menstrual flow. Iron intake was significantly higher in the obese group (15.9 +/- 2.9 vs 14.1 +/- 2.9 mg/d, P less than 0.05). These results suggest that obese menstruating women are at low risk of depleting iron stores, possibly because of high iron intake. Iron-fortification programs might thus be undesirable in such subjects.

Reproducible measurement of postprandial energy expenditure in young healthy males.

The reproducibility of measurements of postprandial energy expenditure (PEE) was determined by assessing, for 345 min, the diet-induced thermogenesis (DIT) of a 4055-kJ mixed meal in 10 lean young men on four occasions. The DIT was determined by using either a 20-min premeal baseline metabolic rate (method 1) or a single resting metabolic rate (RMR) measured on a separate day (method 2). The DIT, in kilojoules, for a given subject calculated by method 1 varied significantly between occasions, CV 15.4% (P < 0.05). The D peak (PEE peak minus baseline) did not vary significantly between the four trials (CV 13%). The results obtained by using method 2 were much more reproducible for both the DIT (CV 4.2%) and the D peak (CV 4.8%). Thus, the reproducibility of the PEE measurement is enhanced by using an RMR measured on a separate day and by using the postprandial peak value instead of the DIT.

Increase in diet-induced thermogenesis at the start of refeeding in severely malnourished anorexia nervosa patients.

Many reports describe the difficulty for anorexia nervosa patients to gain weight during refeeding. To assess whether an increase in diet-induced thermogenesis (DIT) participates to this resistance, we studied DIT by indirect calorimetry in 11 severely malnourished anorexia nervosa patients [body mass index (BMI; in kg/m2) = 13] to accomplish two purposes: 1) to compare DIT in a strict semistarvation state with that obtained after 1 wk refeeding, when metabolism is shifted to a dynamic trend toward regaining weight, without significant change in body composition; 2) to study the effect on DIT of two energetic loads representing each one-third of the energy intake during semistarvation and refeeding, respectively: 1.25 and 2.92 MJ. To avoid bias, the two liquid loads were infused intragastrically in a random double-blind fashion. A significant increase in DIT during refeeding was observed for the two loads (204 +/- 23 kJ for the 1.25-MJ liquid meal and 482 +/- 78 kJ for the 2.92-MJ one, P < 0.02). The higher the load, the larger the increase with refeeding (P < 0.001). This increment in DIT exceeded the increase in active lean body mass and was poorly correlated with lean body mass. These results provide clear evidence of a strong cellular "waste" mechanism in anorexia nervosa patients during the early phase of refeeding, which enhances the adaptative resistance to overfeeding that we have already shown for resting energy expenditure.

Fat-free mass estimation by the two-electrode impedance method.

In 202 healthy subjects (81 men, 121 women) aged 12-71 y, impedance (Z) was measured with a two-electrode analyzer. Fat-free mass was assessed by hydrodensitometry (FFMd). This population was randomized into two groups for cross-validation. In group 1 the relationship between ht2/Z at 1 MHz and FFMd was highly significant (r = 0.85, P less than 0.001). The equation for predicting FFMd from impedance, height2, weight, and age obtained in group 1 (r = 0.97) was applied to group 2 (r = 0.96) without reduction in r value. The accuracy of this equation was not different between men and women or between active and sedentary people. These data indicate that the two-electrode impedance method is a reliable and valid approach not only for the determination of extracellular water (as previously shown) but also for that of FFM.

Energy-metabolism adaptation in obese adults on a very-low-calorie diet.

In this study, six obese women received a very-low-calorie diet (VLCD) for 3 wk. At day 0, body composition was assessed with a bioelectric impedance analyzer. The evolution in lean body mass (LBM) during the VLCD was estimated from nitrogen balance, measuring urine and fecal losses and taking into account skin, nitrate, and menstrual losses to avoid underestimation bias that could explain the decreased ratio of resting metabolic rate (RMR) to LBM previously reported. RMR was measured at days 0, 3, 5, and 21. The RMR-LBM ratio declined significantly during the VLCD period and decreased faster during the first week; the day 3, day 5, and day 21 ratio values were 94%, 91%, and 82%, respectively, of the original. The RMR-LBM ratio decrease after 21 d of a VLCD was near that found in chronic undernutrition. Results of previous studies that did not find any drop in the RMR-LBM ratio in obese adults on VLCDs might be explained by their LBM-assessment methods.

Massive overfeeding and energy balance in men: the Guru Walla model.

To determine the magnitude of the thermogenic response to a massive long-term overfeeding, an energy-balance study was carried out in nine lean, young Cameroonian men participating in a traditional fattening session: the Guru Walla. Food intake, body weight, body composition, activity, and metabolic rates were recorded during a 10-d baseline period and over the 61-65 d of fattening. Total energy expenditure (TEE) was measured by using doubly labeled water during the baseline period and the final 10 d of Guru Walla. Cumulative overfeeding consisted of 955 +/- 252 MJ (chi +/- SD) mainly as carbohydrate. Body-weight increase was 17 +/- 4 kg, 64-75% as fat. Metabolic rates increased but TEE did not. However, when accounting for the reduction in physical activity, substantial thermogenesis was observed but its amplitude was not greater than that observed under less extreme carbohydrate-overfeeding conditions. If luxuskonsumption does exist, it is not related to the magnitude of the cumulative overfeeding.

Lowering of HDL2-cholesterol and lipoprotein A-I particle levels by increasing the ratio of polyunsaturated to saturated fatty acids.

The protective role of high-density lipoproteins (HDLs) has been attributed to the subfractions HDL2 (according to the density) and lipoprotein A-I (LpA-I) (according to the composition in apolipoproteins). We investigated the effect of a high ratio of polyunsaturated to saturated fatty acids (P:S) on these subfractions in a homogeneous group of young adult males. Two prescribed diets were consumed successively at the subjects' homes for 3 wk each in a random order; one diet contained 70 g butter (P:S 0.2, diet B), the other contained 70 g sunflower margarine (P:S 1.1, diet M). Total calorie, fat, and cholesterol intakes were similar for the two diets. Cholesterol and apolipoprotein B in serum and in low-density lipoproteins (LDLs) were lower with diet M than with diet B. However, significant decreases in protective subfractions of HDL, HDL2, and LpA-I were observed. This undesirable effect of the diet with a high P:S could cancel the benefits of lowering the LDL-cholesterol concentrations.

Comparing the effects of aspartame and sucrose on motivational ratings, taste preferences, and energy intakes in humans.

This study compared the effects of four breakfast preloads on motivational ratings, taste preferences, and energy intakes of 24 normal-weight nondieting young men and women. The preloads, composed of creamy white cheese (fromage blanc), were either plain or sweetened with aspartame or sucrose. Their energy value was either 1255 or 2929 kJ (300 or 700 kcal). Taste preferences were measured before and 150 min after breakfast. Motivational ratings were obtained at 30-min intervals. The subjects ate lunch, snack, and dinner meals in the laboratory. The consumption of low-energy as opposed to high-energy breakfasts, regardless of sweetness, led to elevated motivational ratings and increased energy intakes at lunch. However, intakes at subsequent meals were the same for all preloads, and no overall compensation in energy was observed. Aspartame did not promote hunger or lead to increased energy intakes in normal-weight subjects.

Effects of slimming and composition of diets on VO2 and thyroid hormones in healthy subjects.

Oxygen consumption and plasma thyroid hormone concentrations are modified by both low- and high-calorie diets. It has been suggested that the trigger may be changes in weight ("adipostatic" hypothesis involving the difference between the actual weight and the "set point") or changes in amount of carbohydrate in the diet ("carbohydrate" hypothesis). Two experiments were performed in order to test both hypotheses. Fourteen young healthy volunteers were studied: 1) at their spontaneous stable weight; 2) while losing weight rapidly on a calorically restricted diet; 3) and then at their stable new weight when consuming a refeeding diet. The calorie restricted diet resulted in decrease of VO2, and T3, and an increase of rT3; the refeeding diet resulted in values of VO2, T3, and rT3 intermediate between those of the spontaneous diet and those of the restricted diet. Another group of nine subjects were studied at their spontaneous caloric and proteic levels, comparing a diet containing only protein and carbohydrate with a diet containing only protein and fat. During the low carbohydrate diet rT3 increased and T3 decreased but they remained unchanged during the carbohydrate-rich diet. Thus neither the adipostatic hypothesis nor the carbohydrate hypothesis is sufficient alone to explain the observed changes in serum T3 and rT3.

n-3 polyunsaturated fatty acids raise low-density lipoproteins, high-density lipoprotein 2, and plasminogen-activator inhibitor in healthy young men.

The effects of a moderate supplementation in n-3 polyunsaturated fatty acids (PUFAs) were investigated in 36 young healthy adult males. Factors investigated were lipoprotein (including HDL subfractions and apolipoproteins) and hemostasis indexes, assessed by platelet aggregation and plasminogen-activator-inhibitor (PAI) activity. Fat-controlled diets were prescribed, one with and one without a fish-oil supplement (control diet), successively during 3 wk in random order. Total calorie, fat, and cholesterol intakes were similar in the two diets. Triglycerides in serum and very-low-density lipoproteins were lower and high-density-lipoprotein 2 cholesterol was higher with the n-3 PUFA-supplemented diet. These effects as well as a significant decrease in platelet aggregation can be considered beneficial in terms of cardiovascular risk. However, significant increases in low-density-lipoprotein cholesterol and PAI activity occurred and were correlated. This latter effect could be detrimental.

Mechanisms of decreased food intake during weight loss in adult Crohn's disease patients without obvious malabsorption.

Because weight loss is common in colonic Crohn's disease and is poorly correlated with disease activity, we analyzed food intake in 63 patients without malabsorption, 30 patients with weight loss (9.2 +/- 4.2 kg), and 33 patients without weight loss. Energy and protein intakes were lower in patients with weight loss than in those with stable weight (P < 0.01). In the former group, food restrictions were more numerous (P < 0.01) and visual analog scales showed less hunger, decreased appetite, and fewer sensations of pleasure related to eating, as compared with the other group (P < 0.01). Food intake reduction was also related to depressive mood and medical advice. However, there was no difference between groups in fecal energy wasting and resting energy expenditure. Weight loss in Crohn's disease may be due to a decrease in food intake rather than to an increase in energy cost of the disease. Thus, focus of attention on the diet is crucial to prevent malnutrition.

Resting energy expenditure is increased in stable, malnourished HIV-infected patients.

Resting energy expenditure (REE) was measured by reference to body composition in 50 malnourished patients with human immunodeficiency virus (HIV) infection and compared with that of 14 healthy subjects. Among HIV patients, 40 had acquired immune deficiency syndrome (AIDS) and 10 had AIDS-related complex (ARC). All were in stable condition and had a previous history of progressive wasting, ie, a mean body weight loss of 14.2 +/- 8.1 kg over 16.6 mo (range 2-49 ms). The mean REE was 14% higher than estimated basal energy expenditure (EBEE), according to the Harris and Benedict formula. Thirty-four patients (68%) were classified as hypermetabolic (REE greater than 110% EBEE). The best predictable variable for REE was fat-free mass (FFM), as determined by an anthropometric method (r = 0.72; P less than 0.001). The mean REE was 12% higher in HIV patients than in the control group FFM (156 +/- 19 vs 124 +/- 17 kJ.kg FFM-1.d-1). We concluded that in stable and malnourished HIV patients, the progressive wasting may be partly related to an increase in REE. The mechanism of this hypermetabolic state remains to be established.

Lack of association between dietary alcohol and HDL-cholesterol concentrations in obese women.

The relationships of alcohol intake and corpulence to HDL-cholesterol were studied in 653 women taking medical advice about body weight. The body mass index (BMI) was positively correlated with triglyceride and negatively with HDL-cholesterol. The relation between BMI and HDL-cholesterol was discontinuous. Total cholesterol, triglycerides and diastolic blood pressure were increased for alcohol intakes greater than 10 g/d regardless of body weight. Alcohol intake was associated with higher concentrations of HDL-cholesterol (P = 0.006) in non obese (BMI = 25.2 +/- 1.5 kg/m2) subjects, but not in mildly (27.3 less than or equal to BMI less than 32.3) or massively (BMI greater than or equal to 32.3) obese subjects. The fact that HDL concentrations were not associated with alcohol intake in obese patients suggests that (1) alcohol acts on the HDL pool through one of the pathways which are perturbed in obesity, possibly lipolysis, (2) obesity is one of the reasons for the differences in individual responses of HDL-cholesterol to alcohol, (3) myocardial infarction might not be inversely correlated with alcohol intake in the obese as it is in the non-obese population.

Time-course, magnitude and nature of the changes induced in HDL by moderate alcohol intake in young non-drinking males.

The effects of moderate alcohol intake on the lipoprotein profile were evaluated in 10 normolipemic abstinent male subjects aged 18-21 years. The experimental period lasted 4 weeks during which 30 g of alcohol were ingested daily as red table wine. It was preceded and followed by 3 weeks of total abstinence. Lipoproteins were analyzed by gradient ultracentrifugation at the end of each abstinence period and weekly during the experimental period, to follow the time-course of alteration. Total HDL were increased by 25% (range 14-72%) during the first 2 weeks of alcohol, lighter HDL3, but not HDL2, exhibiting a greater response than other classes. The effect of alcohol regressed with time and by the 4th week mean HDL levels were only 14% higher than prior to treatment. HDL levels returned to normal on weaning. The wide variations in individual responses were consistent over the experimental period and are suggestive of differences in individual susceptibility.

Low high density lipoprotein-2 concentrations in obese male subjects.

In this study we have compared the lipoprotein patterns, in particular HDL subfractions, of 34 obese men to those of 34 normoponderal normolipemic men, matched for age and use of tobacco. Obesity was associated with increased VLDL concentrations in only half the subjects. HDL concentrations in all obese subjects were lower than in matched controls. The decrease was most marked in the HDL2 subfraction in which cholesterol and protein contents were decreased by 50%; it was independent of triglyceride levels and not related to the severity of overweight. Moreover, while HDL2 was negatively correlated with BMI (P less than 0.01) when both populations were considered together, the correlation disappeared when calculated separately within each population, suggesting a threshold effect. The low levels of HDL2 might result from discretely altered lipolysis, not sufficient to cause an elevation in fasting triglyceridemia. In this case, HDL2 should prove to be a sensitive index of lipolytic efficiency.

Long-term maintenance of weight loss after a very-low-calorie diet: a randomized blinded trial of the efficacy and tolerability of sibutramine.

BACKGROUND: Very-low-calorie diets are a well established method to achieve substantial short-term weight loss in obese patients, but long-term maintenance of the weight loss is very disappointing. A combined very-low-calorie diet and pharmacologic approach could be an effective means of prolonging its benefits. PATIENTS AND METHODS: Eligible patients had a body-mass index greater than 30 kg/m2; those who lost 6 kg or more during a 4-week treatment with a very-low-calorie diet were randomly assigned to 1 year of treatment with sibutramine (10 mg) or identical placebo. RESULTS: In an intention-to-treat analysis, mean (+/-SD) absolute weight change at 1 year (or study endpoint) was -5.2 (+/-7.5) kg in the 81 patients in the sibutramine group and +0.5 (+/-5.7) kg in the 78 patients in the placebo group (P = 0.004). When compared with their weight at study entry (before the very-low-calorie diet), 86% of patients in the sibutramine group had lost at least 5% of their weight, compared with only 55% of those in the placebo group (P <0.001) at the study endpoint. Similarly, at month 12, 75% of subjects in the sibutramine group maintained at least 100% of the weight loss achieved with a very-low-calorie diet, compared with 42% in the placebo group (P <0.01). CONCLUSION: Following a very-low-calorie diet, sibutramine is effective in maintaining and improving weight loss for up to 1 year.

Beta-adrenergic receptor sensitivity and guanine nucleotide regulatory proteins in transplanted human hearts and autotransplanted baboons.

This study was conducted in human subjects and in baboons to assess elements of the beta-adrenergic receptor complex in vivo and in vitro following cardiac transplantation. In human subjects, the concentration at which administered isoproterenol increased heart rate by 25 beats per min was within the normal range (mean, 3.2 +/- 0.4 micrograms). Myocardial biopsies and lymphocytes were obtained from 14 transplant recipients undergoing routine right heart catheterization. The stimulatory guanine nucleotide regulatory protein, Gs, was significantly greater in the lymphocyte than in right ventricular myocardium (5.8 +/- 1.7 vs. 2.0 +/- 0.5 relative to standard rat heart membrane preparation, P less than 0.05). In contrast, Gi was significantly greater in the myocardium than in the lymphocyte (4.2 +/- 1.3 vs. 1.1 +/- 0.3, P less than 0.025). There was no correlation between lymphocyte and cardiac G protein determinations. In the autotransplanted baboon heart, beta-receptors were increased (73 +/- 4 vs. 36 +/- 10 fmol/mg, P less than 0.05). Gs was not significantly different in denervated myocardial tissue vs. control cardiac tissue (1.1 +/- 0.2 vs. 0.8 +/- 0.2, P greater than 0.05). However, the inhibitory G protein, Gi, was significantly greater in transplanted animals (0.4 +/- 0.1 vs. 0.2 +/- 0.04, P less than 0.05). Relative enrichment of a Gi-like protein in the autotransplanted baboon heart was associated with a non-statistically significant trend towards a uniform reduction in basal and Gs-mediated adrenergic effects on adenylate cyclase activity. Despite the lack of biochemical evidence of enhanced beta-adrenergic receptor-mediated adenylate cyclase coupling, denervation in the autotransplanted baboon was associated with in vitro evidence of chronotropic and inotropic supersensitivity to isoproterenol. The results call into question the notion of adrenergic hypersensitivity in human subjects following cardiac transplantation, indicate the potential role for guanine nucleotide regulatory proteins in mediating responses of the denervated heart, and distinguish between several characteristics of the chronically denervated, transplanted human heart compared with the acutely auto-denervated of the baboon heart.