Digoxin disposition in obesity: Clinical pharmacokinetic investigation

Olgoxin pharmacokinetics were studied in 16 obese (mean ± SD weight, 100.2 ± 36.8 kg) and 13 control (64.6 ± 10.5 kg) subjects. all subjects had normal renal function and no other coexisting disease. After administration of 0.75 mg digoxin by intravenous intusion, multiple plasma samples obtained over the 96 hours following infusion were analyzed for digoxin concentration by radloimmunoassay. Pharmacokinetic parameters were determined by weighted iterative nonlinear least squares regression analysis. Elimination half-life ($\text{t}\text{1}\text{2}$) was not different between obese and control groups (35.6 ± 10.5 vs 41.2 ± 16.7 hours). Absolute volume of distribution (Vd) also was not different (981 ± 301 vs 937 ± 397 liters), nor was total clearance of digoxin (328 ± 82 vs 278 ± 87 ml/min). Elimination $\text{t}\text{1}\text{2}$ was significantly negatively correlated with clearance among all subjects (r = ?0.46; p < 0.01). Using percent ideal body weight (IBW) as a measure of obesity, no correlation was found between percent IBW and Vd (r = 0.03). Thus digoxin is simllarly distributed into IBW in obese and normal weight subjects, and there is no significant distribution of digoxin into excese body weight over IBW. In addition, there is no difference in total metabolic clearance or elimination half-life between obese and control subjects. Digoxin loading and maintenance dosage should be calculated on the basis of IBW, which reflects lean body mass, rather than TBW, which reflects adipose tissue weight in addition to lean body mass.     

Relationship of plasma sex hormones to different parameters of obesity in male subjects

Relationships between plasma sex hormones and different parameters of obesity (weight, ideal body weight [IBW], overweight, fat mass, and body surface) were investigated in 70 healthy nonobese and obese males, 20–40 yr of age and with a body weight of 85%–245% of IBW. Plasma sex hormones remained unaffected by weight up to approximately 160% of the IBW. Only in the massively obese subjects was plasma testosterone decreased to 40% of controls (from 6.2 to 2.5 ng/ml), whereas free testosterone remained almost constant. On the other hand, plasma estrone and estradiol exhibited significant increases in obese subjects, ranging from 31.5 ± 5.3 to 52.3 ± 5.8 pg/ml for estrone, and 25.4 ± 5.4 increasing to 44.7 ± 5.0 pg/ml for estradiol. Similarly, free estradiol was shown to significantly increase with obesity in men from 505 ± 118 to 991 ± 123 fg/ml (p < 0.001). The ratios of testosterone/androstenedione, as well as of estradiol/estrone, were not affected by obesity, suggesting that reduction of the 17-oxo-group of the steroids is not influenced by the amount of fat tissue. A significant (p < 0.001) correlation was found between IBW and estrone (r = 0.80) and estradiol (r = 0.75), as well as the ratios of estrone/androstenedione (r = 0.62) and estradiol/testosterone (r = 0.86). This is consistent in its evidence indicating that fat tissue may be able to aromatize androgens. In the obese subjects, there were significant correlations between plasma sex hormones (testosterone, estrone, estradiol, and free estradiol) and the parameters of obesity used. Among these, correlations were best with IBW, overweight, and fat mass (r = 0.74–0.89; p < 0.001); body weight and body surface were less favorable.     

Sex and insulin sensitivity

To analyze whether enhanced adiposity in females as compared with males is associated with a decreased sensitivity to insulin, a group of healthy normal weight females (n = 13, age 21 ± 1 years) and males (n = 11, age 23 ± 1 year, mean ± SEM) was studied. In each subject, body composition (% fat and % muscle), maximal aerobic power (V_O2 max) and whole body insulin-mediated glucose metabolism were measured. The group of women had a higher percentage of fat to total body weight (P < 0.001) and a lower percentage of muscle (P < 0.001) than the group of men. The higher percentage of fat in women compared with males was due to enhanced peripheral fat accumulation in the arm and thigh regions. V_O2 max levels were comparable in both groups (48 ± 1 mL/kg/min for women, 53 ± 2 mL/kg/min for men, P = NS). The rate of glucose metabolism (M) was comparable in women (8.78 ± 0.74 mg/kg/min), and men (8.31 ± 0.89 mg/kg/min) when expressed per kilogram of total body weight, but when expressed per kilogram of muscle tissue (M_m), it was 45% higher in women (29.4 ± 2.4 mg/kg/min) than in men (20.2 ± 1.6 mg/kg/min, P < 0.005). Partial correlation analysis indicated that the percentage of fat was inversely related to M and M_m in both women (P < 0.05) and men (P < 0.05), but not to percentage of muscle or V_O2 max. Conclusions: (1) Insulin-mediated glucose disposal is inversely related to adiposity in normal weight healthy males and females. (2) Women and men utilize equal amounts of glucose despite a higher adiposity in females. (3) Since muscle tissue utilizes most of intravenously administered glucose, this result indicates enhanced glucose uptake by muscle tissue in females compared with males. (4) Elevated glucose uptake by muscle in women may provide a mechanism by which women are protected against excessive hyperglycemia despite their smaller amount of glucose-consuming tissue.     

Impaired skeletal muscle nutritive flow during exercise in patients with congestive heart failure: Role of cardiac pump dysfunction as determined by the effect of dobutamine

The maximal exercise capacity of patients with congestive heart failure (CHF) is frequently reduced, partly because of inadequate skeletal muscle nutritive flow. To investigate whether this altered muscle nutritive flow is a result of inability of the heart to increase cardiac output normally during exercise, the effect of dobutamine on systemic and leg blood flow and metabolism during maximal exercise was examined in 11 patients with CHF. At maximal exercise before dobutamine, all patients were limited by fatigue and had reduced maximal systemic oxygen uptake (11.9 ± 1.1 ml/min/kg) (± standard error of the mean), markedly elevated leg oxygen extraction (85 ± 2%) and elevated femoral venous lactate (53 ± 5 mg/dl), consistent with impaired nutritive flow to working muscle. Dobutamine increased the peak cardiac output from (6.5 ± 0.9 to 7.4 ± 0.7 liters/min, p < 0.01) and peak leg flow (from 1.7 ± 0.3 to 2.1 ± 0.3 liters/min, p < 0.05) during exercise. In contrast, no change occurred in maximal exercise duration (5.5 ± 0.8 vs 5.8 ± 0.8 min), peak systemic VO₂ (829 ± 97 vs 869 ± 77 ml/min), peak arterial lactate (34 ± 2 vs 35 ± 4 mg/dl) or peak leg lactate output (248 ± 39 vs 275 ± 53 mg/min), whereas peak leg oxygen extraction decreased (85 ± 2 to 80 ± 2%, p < 0.01), suggesting no improvement in muscle nutritive flow. These data suggest that nutritive flow to working skeletal muscle is impaired in patients with CHF and that this impairment is not due simply to an inability of the heart to increase the cardiac output normally during exercise.     

Normal valine disposal in obese subjects with impaired glucose disposal: Evidence for selective insulin resistance

Insulin has major effects on both glucose and branched chain amino acid metabolism. To determine whether the insulin resistance of obesity equally affects both glucose and branched chain amino acid metabolism, we measured the ability of obese and normal subjects to dispose of intravenous bolus doses of glucose (25 g) or L-valine (4 g). Basal plasma glucose levels were the same in the 18 normal and 17 obese (163 ± 8% of ideal body weight) subjects, but basal plasma insulin levels were higher in the obese group (15 ± 2 vs 6 ± 1 μU/ml; p < 0.001). The obese group had a slower glucose disappearance rate after glucose challenge (0.84 ± 0.06 vs 1.11 ± 0.07 hr^?1; p < 0.01) despite having a greater serum insulin response to the glucose load (26 ± 4 vs 11 ± 1 insulin area units; p < 0.01), confirming insulin resistance. In contrast, disposal of a valine load was the same in normal and obese subjects, as assessed by initial and second phase exponential disappearance rates, metabolic clearance rates of valine, and volumes of distribution. In normal men, disposal rates of glucose and valine after simultaneous administration of both substances were slower than corresponding disposal rates determined when each substance was given alone. We conclude that obese subjects with impaired glucose disposal have normal valine disposal, suggesting that the insulin resistance of obesity can be selective in its effect on different metabolic systems. Glucose and valine also appear to mutually antagonize each other's disposal.     

Effects of nitroglycerin on supine and upright exercise in mitral stenosis

Resting, supine, and upright exercise hemodynamics were studied in 11 patients with pure or predominant mitral stenosis before and after 0.4 mg sublingual nitroglycerin. Resting mean pulmonary wedge pressure was reduced from 27 ± 1.6 to 21 ± 1.6 mm Hg (p < 0.001), while mean cardiac index (2.98 ± 0.40 vs 2.68 ± 0.30 cc/min/m²; NS) and mean heart rate (82 ± 4.4 vs 87 ± 6.7 bpm; NS) were unchanged after nitroglycerin. Resting mean left ventricular end-diastolic pressure dropped from 11 ± 1.7 to 8 ± 1.1 mm Hg (p < 0.02) after nitroglycerin, while stroke index (37 ± 5.1 vs 32 ± 3.8 mm Hg; NS) was unchanged. Left ventricular systolic pressure fell from 122 ± 6.0 to 111 ± 3.1 mm Hg (p < 0.001) after nitroglycerin. At peak supine exercise similar qualitative changes were observed. Mean pulmonary wedge pressure was lower after nitroglycerin (43 ± 2.3 vs 36 ± 2.1 mm Hg; p < 0.02), while cardiac index (3.62 ± 0.39 vs 3.4 ± 0.26 cc/min/m²; NS) and heart rate (116 ± 7.1 vs 113 ± 4.6 bpm; NS) were not different. Left ventricular end-diastolic pressure (13 ± 1.4 vs 10 ± 1.3; NS) was slightly but not significantly reduced by nitroglycerin. Left ventricular stroke index (34 ± 3.4 vs 31 ± 2.2 mm Hg; NS) was unchanged by nitroglycerin. Left ventricular systolic pressure (137 ± 7.3 vs 127 ± 6.1 mm Hg; p < 0.02) was reduced 10 mm Hg at peak supine exercise after nitroglycerin. During upright exercise, peak heart rate (160 ± 8.1 vs 160 ± 8.0 bpm; NS) and peak systolic blood pressure (117 ± 5.7 vs 112 ± 2.8 mm Hg; NS) were not changed with nitroglycerin. Exercise duration was improved after introglycerin (5.02 ± 0.62 vs 5.66 ± 0.65 minutes; p < 0.02). Thus sublingual nitroglycerin lowers mean pulmonary wedge pressure to reduce pulmonary congestive symptoms, improves supine exercise hemodynamics, and may enhance treadmill exercise duration in some patients with pure or predominant mitral stenosis.     

The impact of obesity on balance control in community-dwelling older women

Older individuals have impaired balance control, particularly those that are frail and/or have sensory deprivations. Obese individuals show faster body sway during upright stance than normal weight individuals, suggesting that they also have difficulty controlling balance even if they do not have the same sensory issues as the older people. Therefore, the objective of this study was to examine if obesity is associated to a decreased balance control in older women. Postural sway of normal weight (n?=?15, age?=?70.8?±?5.5 years; BMI?=?22.2?±?1.9 kg/m²), overweight (n?=?15, age?=?71.7?±?4.3 years; BMI?=?27.3?±?1.3 kg/m²), and obese (n?=?15, age?=?71.1?±?4.3 years; BMI?=?33.1?±?3.4 kg/m²) women was measured with a force platform for normal quiet stance lasting for 30 s in opened and closed eyes conditions. The obese group oscillated at a faster speed than the normal weight group (vision 0.99?±?0.29 cm/s vs. 0.70?±?0.16 cm/s, p?<?0.01; no vision 1.43?±?0.50 cm/s vs. 0.87?±?0.23 cm/s, p?<?0.01). The obese group exhibited greater range in both axes without vision compared to the normal weight group (p?<?0.05). When observing sway density parameters, the obese group also spent less time in stability zones (2 mm radius area in which the center of pressure is relatively stable), and the distance between these stability zones are greater than the normal weight group in both visual conditions (p?<?0.01 and p?<?0.05, respectively). Obesity clearly affects postural control in older women. Our results suggest that obesity has a negative impact on the capacity of older woman to adequately use proprioceptive information for posture control. As postural instability or balance control deficits are identified as a risk factor for falling, our results also suggest that obesity in older women could be considered as another potential contributing factor for falling.     

Sex difference in the influence of obesity on the retention of a tracer of 3H-estradiol

The influence of obesity on the retention of a tracer of ³H-estradiol was studied in 15 nonobese premenopausal women, 15 obese premenopausal women (49%–274% above desirable weight), and 27 young men ranging in weight from 5% below to 330% above desirable weight. The women showed a clear-cut inverse linear correlation between the 72 hr excretion of radioactivity and the percent deviation from desirable weight over the entire weight range examined (y = 66 ? 0.10x, r = ?0.59, P < 0.005); the average excretion in the 6 most obese women (145%–274% above desirable weight) was 45 ± 11 (SD)%, significantly lower than the value of 65 ± 12% in 15 nonobese women (P < 0.025). The obese men showed no correlation whatever between excretion of radioactivity and relative body weight; the average excretion of the 6 most obese men was 55 ± 7, not significantly different from the value of 56 ± 12 in nonobese men. This sex difference makes untenable the hypothesis previously proposed by others that retention of estradiol tracers in obese women (men were not studied) is due to simple solubility of estrogens in fat. Various alternative possibilities to explain the present data are discussed and it is concluded that a possibility worth examining is that the adipose tissue of women contains specific estrogen binding protein (? receptor) while the adipose tissue of men does not.     

Abnormal body composition and reduced bone mass in growth hormone deficient hypopituitary adults*

OBJECTIVES The role of growth hormone in maintaining normal body composition and bone strength In adults has attracted much interest recently. We have assessed body composition and bone mass in GH deficient hypopituitary adults on conventional replacement therapy and compared them with matched controls. DESIGN AND SUBJECTS A cross-sectional Study Of 64 growth hormone deficient hypopituitary adults (29 males and 35 females) on conventional replacement therapy and a large number of healthy control subjects matched for age, sex and body mass index (BMI). MEASUREMENTS Skinfold thicknesses at two sites (triceps and subscapular), waist and hip girth circumferences were assessed by standard methods. Body composition was assessed using total body potassium (TBK), bioelectrical impedance analysis (BIA) and dual-energy X-ray absorptiometry (DEXA). Bone mineral mass was assessed at the lumbar spine and the total body by DEXA. Not every patient and control participated In every measurement. RESULTS Obesity was common in the hypopituitary patients; BMI (mean±SD) was 27·5 ± 4·6 kg/m² and body weight was 111·8 ±185% of the maximal ideal for height (P< 0·001). The sum of subscapular and triceps skinfolds was significantly higher in hypopituitary patients than in controls (men 46+15 vs 37±14mm, P<0·05; women 55±13 vs 47±17mm, P<0·05). Waist to hip circumference ratio was significantly greater In female hypopituitary patients than in matched controls but was not significantly different in men (men 0·94± 0·07 vs 0·91 ± 0·07, NS; women 0·84±0·09 vs 0·77±0·05, P < 0·001). The difference between patients and controls in the sum of skinfolds and the waist to hip ratio were present In non-obese (BMI < 26 kg/m²) subjects (21 patients and 32 controls). TBK corrected for body weight was significantly lower In hypopituitary patients (n= 44) than in controls (n= 31) (men 43·±5.6 vs 50·1 ± 5·9 mmollkg, P < 0·003; women: 34·0 ± 3.2 vs 40·6 ± 5·3 mmol/kg, P < 0.0001). BIA-derived body water content (corrected for body weight) was significantly lower In hypopituitary patients (n= 56) than in controls (n= 57) (0·492 ± 0·064 vs 0·545 ± 0·067 1/kg, P < 0.0004). Percentage body fat derived from ail the three methods was significantly higher in hypopituitary patients than in normal controls In both sexes (from TBK men 34·7 ± 94 vs 28·8 ± 7·0%, P < 0·05; women 37·8 ± 8·7 vs 30·4 ± 9·7%, P < 0·01; from BIA men 29·3 ± 8·5 vs 23·2 ± 8·4%, P < 0·01; women 34·6 ± 8.1 vs 29·3 ± 9·1%P < 0·01; and from DEXA: men 24·8 ± 6·8 vs 20·4 ± 6·1 %, P < 0·05; women 38·9 ± 7·9 vs 32·5 ± 9·8%, P < 0·01). There was a significant difference between non-obese patients and controls in BIA-derived percentage fat in both sexes and in TBK-derived percentage fat In females only. Bone mineral density (BMD) of the lumbar spine in the L2-L4 region was lower in hypopituitary patients than in controls (men 1·116±0·129 vs 1·311 ± 0·131 g/cm², P <0·0001; women 1·001 ±0·122 vs 1·131 ±0·138g/cm², P < 0·001). Spine BMD was also reduced in hypopituitary patients compared to the young adult and age and weight matched reference data. Total body BMD was significantly lower in patients than In controls (men 1·186 ± 0·102 vs 1·250 ± 0·080 g/cm², P < 0·05; women 1·080 ± 0·077 vs 1·149 ± 0·073 g/cm², P < 0·005). CONCLUSIONS Hypopituitary adults on conventional therapy have abnormal body composition with increased fat content, reduced body water content and reduced bone mineral mass     

Hemodynamic effects of nifedipine in congestive heart failure

Nifedipine, a potent coronary vasodilator, was administered in a single sublingual dose of 20 mg to eight patients with mild to moderate congestive heart failure. Nifedipine produced a slight increase in heart rate (mean ± standard error of the mean 73.3 ± 3.2 versus 80.9 ± 2.1 beats/min, p <0.025) and an increase in cardiac index (from a control value of 3.51 ± 0.22 to 4.06 ± 0.31 liters/min per m², p <0.01). Arterial blood pressure decreased from $\text{112.9 ±}\text{6.2}\text{67.7 ± 4.2}\text{(}\text{mean}\text{84.9 ± 4.0)}\text{to}\text{100.8 ±}\text{4.4}\text{56.4 ± 11.0}\text{(}\text{mean}\text{76.1 ± 4.3)}$ mm Hg (p <0.01) and total systemic vascular resistance also decreased from a control value of 15.6 ± 1.0 to 12.4 ± 0.8 units (p <0.01) after administration of nifedipine. These data suggest that nifedipine may be useful for vasodilation in congestive heart failure.     

Effects of acute exercise on insulin binding to monocytes in obesity

The effect of 3 hr of cycle erogmeter exercise on ¹²⁵I-insulin binding to monocytes was studied in 8 obese and 10 nonobese control subjects. In the basal state before exercise, total specific ¹²⁵I-insulin binding to monocytes in obese subjects (4.8% ± 0.3%) was 25% lower than in control subjects (6.6% ± 0 0.4%, p < 0.01). During exercise, insulin binding increased in both groups (p < 0.05), but the rise in obese subjects was minimal (13% ± 1%) and was 60%–70% lower than in controls (36% ± 3%, p < 0.01). The data indicate that the increment in insulin binding to monocytes induced by acute exercise is diminished in obesity.     

Sex difference in the influence of obesity on the 24 hr mean plasma concentration of cortisol

The 24 hr mean plasma cortisol concentration was measured in 65 healthy women ranging from 21% below to 218% above desirable weight and in 47 healthy men ranging from 5% below to 330% above desirable weight. In the women, there was a clear-cut inverse linear correlation between the plasma cortisol concentration and the percent deviation from desirable weight (y = 7.5 ? 0.3 x; r = ?0.49; p < 0.001); the relation of free to total cortisol concentration was weight-invariant; the MCR of cortisol in the most obese women was much higher than that of nonobese women (340 ± 76 versus 211 ± 31 liters/gm urinary creatinine; p < 0.01). In the men, the plasma cortisol level and MCR were weight-invariant. To account for the finding in women of a linear correlation of the decrement in plasma cortisol level with the percent deviation from desirable weight (which in turn is nearly perfectly correlated with the total body fat content), we postulate that a given weight of adipose tissue in women takes up a constant amount of cortisol; this in turn suggests that their adipose tissue contains a saturable binding system such as corticosteroid receptor. By the same logic, the weight-invariance of plasma cortisol and MCR in men suggests the absence of significant amounts of corticosteroid receptor in their adipose tissue. The finding that the increased cortisol MCR of obese women results in decreased plasma cortisol levels rather than an increase in cortisol production (the latter, corrected for muscle mass, is normal in obesity: Strain et al, Metabolism 29:980, 1980) suggests a defect in their cortisol ACTH feedback system. Such a defect, presumably hypothalamic, is not unexpected in the light of reports of defective hypothalamic control of prolactin and growth hormone secretion in obesity.     

Increase in skeletal muscle fatty acid binding protein (FABPC) content is directly related to weight loss and to changes in fat oxidation following a very low calorie diet

Aims/hypothesis: There is increasing evidence that intracellular fatty acid binding proteins (FABPc's; 15 kD) function as vehicles of cytosolic fatty acid transport. We studied skeletal muscle cytosolic FABPc, and enzymes reflecting β-oxidation and oxidative capacity (3-hydroxyacyl-CoA dehydrogenase, HAD, and citrate synthase, CS) in relation to weight loss and changes in substrate utilisation in a group of 35 obese women and obese men with Type II (non-insulin-dependent) diabetes mellitus (women = 27, men = 8). Methods: Muscle biopsies (vastus lateralis), and measurements of body composition, resting energy expenditure and respiratory exchange ratio were taken before and after dietary intervention (by means of a very low calorie diet). Results: Muscle FABPc tended to increase after diet (178 ± 13 vs 204 ± 12 mg^.gww^–1, p = 0.06), whereas there were no changes in CS (10.5 ± 0.7 vs 11.1 ± 0.6 U^.gww^–1) and HAD (11.2 ± 0.7 vs 11.7 ± 0.6 U^.gww^–1). There was a positive relation between the increase in FABPc as result of diet and the amount of weight lost (p < 0.01; adjusted R², 15.4 %), even when adjusted for mean body weight, and changes in CS and in HAD by partial regression analysis. Interestingly, the increase in FABPc was positively related to increases in resting fat oxidation (adjusted R², 24 %), even when adjusted for mean resting fat oxidation, and changes in CS and in HAD. Conclusion/interpretation: In conclusion, the ability to increase muscle FABPc could be directly related to weight loss and to changes in fat oxidation following dietary intervention in obesity and Type II (non-insulin-dependent) diabetes mellitus. [Diabetologia (2001) 44: 2013–2017] Received: 4 May 2001 and in revised form: 17 July 2001     

Whole-body Glucose Metabolism in Obese Patients with Type 2 Diabetes Mellitus: the Impact of Hypertension and Strict Blood Glucose Control

We have examined the impact of hypertension and blood glucose control on insulin sensitivity in obese Type 2 (non-insulin-dependent) diabetic patients. Glucose metabolism in the basal state and in response to insulin was examined using the euglycaemic, hyperinsulinaemic (2 mU kg^?1 min^?1) clamp technique in combination with 3-[3H]-glucose infusion and indirect calorimetry in 60 obese Type 2 diabetic patients (30 normotensive patients and 30 hypertensive patients on antihypertensive treatment) and 10 obese normotensive control subjects. In the basal state and during hyperinsulinaemia, glucose disposal rates (total, oxidative, and nonoxidative) were similar in Type 2 diabetic patients with or without hypertension (230 ± 83 vs 270 ± 114 mg m^?2min^?1 (NS), 83 ± 28 vs 95 ± 7 mg m^?2 min^?1 (NS), 148 ± 70 vs 180 ± 89 mg m^?2 min^?1 (NS), treated hypertensive vs normotensive subjects, respectively). However, compared to obese control subjects (403 ± 65 mg m^?2 min^?1) both groups of diabetic patients had significantly decreased insulin-stimulated glucose disposal rates (p < 0.005). Even in a subset of Type 2 diabetic patients with long-term (> 6 months) near normal blood glucose control (HbA_1c < 6.1 %) significant defects were detectable in whole-body glucose and lipid metabolism when compared to control subjects. These results indicate that treated hypertension does not significantly aggravate the insulin insensitivity that is already present in Type 2 diabeted mellitus. Furthermore, Type 2 diabetic patients with long-term good metabolic control continue to demonstrate insulin insensitivity in peripheral tissues.     

Prostacyclin therapy in patients with congestive heart failure

The acute hemodynamic effects of intravenous prostacyclin (PGI₂), in doses of 22 ± 11 ng/kg per min were studied in nine patients with severe congestive heart failure refractory to digitalis and diuretic drugs. After prostacyclin infusion, mean (±standard deviation) pulmonary capillary wedge pressure decreased from 21.0 ± 7.9 to 15.0 ± 6.6 mm Hg (p < 0.001), mean arterial pressure from 98.9 ± 12.8 to 76.2 ± 7.0 mm Hg (p < 0.001), systemic vascular resistance from 2,574 ± 384 to > 1,368 ± 283 dynes s cm^?5 (p < 0.001), pulmonary vascular resistance from 1,008 ± 451 to 443 ± 135 dynes s cm^?5 (p < 0.001) and pulmonary arteriolar resistance from 330 ± 111 to 189 ± 73 dynes s cm^?5 (p < 0.001). Heart rate increased from 78 ± 21 to 82 ± 24 beats/min (p = not significant [NS]), cardiac index from 2.0 ± 0.37 to 3.2 ± 0.59 liters/min per m² (p < 0.001) and stroke index from 27.6 ± 8.69 to 42.0 ± 0.62 cc/m² (p < 0.001). With prostacyclin, moreover, coldness of the limbs and face disappeared, and patients felt warmth and mild flushing of the face. After prostacyclin, plasma norepinephrine levels, renin activity and aldosterone concentrations rose from 824 ± 375 to 880 ± 468 pg/ml (NS), 0.68 ± 1.36 to 0.95 ± 1.21 ng/ml per h (NS), and 6.64 ± 2.50 to 6.38 ± 2.88 ng/dl (NS), respectively, while plasma epinephrine increased from 140 ± 80 to 250 ± 154 pg/ml (p < 0.025).     

Adipose tissue is inflamed in NAFLD due to obesity but not in NAFLD due to genetic variation in PNPLA3

Aims/hypothesis

The rs738409 C>G single-nucleotide polymorphism in PNPLA3 leads to a missense mutation (I148M) which increases liver fat but does not cause insulin resistance. We hypothesised that patients with non-alcoholic fatty liver disease (NAFLD) due to the PNPLA3 variant (‘PNPLA3 NAFLD’?=?PNPLA3-148MM) do not have adipose tissue (AT) inflammation in contrast with those with NAFLD due to obesity (‘obese NAFLD’).

Methods

Biopsy specimens of AT were taken, and PNPLA3 genotype and liver fat (¹H-magnetic resonance spectroscopy) were determined in 82 volunteers, who were divided into groups based on either median BMI (obese 36.2?±?0.7 kg/m²; non-obese 26.0?±?0.4 kg/m²) or PNPLA3 genotype. All groups were similar with respect to age and sex. The PNPLA3 subgroups were equally obese (PNPLA3-148MM, 31.1?±?1.3 kg/m²; PNPLA3-148II, 31.2?±?0.8 kg/m²), while the obese and non-obese subgroups had similar PNPLA3 genotype distribution. Gene expression of proinflammatory (MCP-1, CD68) and anti-inflammatory (Twist1, ADIPOQ) markers was measured using quantitative real-time RT-PCR.

Results

Liver fat was similarly increased in obese NAFLD (9.5?±?1.3% vs 5.1?±?0.9%, obese vs non-obese, p?=?0.007) and PNPLA3 NAFLD (11.4?±?1.7% vs 5.3?±?0.8%, PNPLA3-148MM vs PNPLA3-148II, p?<?0.001). Fasting serum insulin was higher in the obese than the non-obese group (76?±?6 vs 47?±?6 pmol/l, p?<?0.001), but similar in PNPLA3-148MM and PNPLA3-148II (60?±?8 vs 62?±?5 pmol/l, NS). In obese vs non-obese, MCP-1 and CD68 mRNAs were upregulated, whereas those of Twist1 and ADIPOQ were significantly downregulated. AT gene expression of MCP-1, CD68, Twist1 and ADIPOQ was similar in PNPLA3-148MM and PNPLA3-148II groups.

Conclusions/interpretation

PNPLA3 NAFLD is characterised by an increase in liver fat but no insulin resistance or AT inflammation, while obese NAFLD has all three of these features.     

Effects of isosorbide dinitrate and hydralazine on regional metabolic responses to arm exercise in patients with heart failure

The reduced exercise capacity of patients with heart failure is thought to be due in part to impaired skeletal muscle oxygen delivery. To determine if hydralazine and isosorbide dinitrate improve skeletal muscle oxygen delivery in such patients, the effects of these agents on regional metabolic responses to forearm exercise were examined in 16 patients with heart failure. Arm oxygen extraction and brachial venous lactate concentration were measured at rest and during 3 minutes of rhythmic handgrip and then remeasured after administration of oral hydralazine (nine patients) or sublingual isosorbide dinitrate (nine patients). Hydralazine increased mean (± standard deviation) cardiac output at rest from 3.5 ± 0.5 to 4.9 ±1.0 liters/min (p < 0.01) and decreased arm oxygen extraction from 39 ± 8 to 33 ± 10 percent (probability [p] < 0.01), suggesting improved resting limb oxygen delivery. However, hydralazine did not reduce arm oxygen extraction during exercise (control 63 ± 4, hydralazine 60 ± 12 percent; p = notsignificant[NS]) or venous lactate during exercise (control 16.6 ± 7.8, hydralazine 17.1 ± 4.8 mg/100 ml; p = NS). Isosorbide dinitrate increased the cardiac output from 3.6 ± 0.7 to 4.5 ± 0.7 liters/min (p < 0.01) but had no effect on arm oxygen extraction at rest (control 40 ± 11, isosorbide dinitrate 38 ± 11 percent; p = NS) and during exercise (control 66 ± 5, isosorbide dinitrate 64 ± 8 percent; p = NS) or on venous lactate during exercise (control 17.9 ± 6.4, isosorbide dinitrate 17.1 ± 3.9 mg/100 ml; p = NS). These data suggest that hydralazine and isosorbide dinitrate do not improve skeletal muscle oxygen delivery during exercise in patients with heart failure.     

Effect of body weight on the volume of distribution of theophylline

The volume of distribution (Vd) of theophylline and the relevant aminophylline loading dose (LD) are usually calculated on the basis of total body weight (TBW). In obese subjects it has been suggested that lean or ideal body weight (IBW) is the best predictor. In a sample of 40 acutely ill asthmatic patients (aged 22 to 78 yr, weighing 45 to 176 kg) we measured Vd and found that (1) it increases with TBW, (2) it cannot be accurately predicted from either TBW or IBW alone by a simple regression analysis. Power functions have been usefully applied in comparing the pharmacokinetics of animal species, including humans, with different body mass. In our sample, data were best fitted by the equation Vd = 1.29 TBW^0.74, which seems to take care of lean as well as obese patients. Results were confirmed (r = 0.89 between predicted and measured values) in a second independent sample of patients (aged 26 to 77 yr, weighing 38 to 167 kg). This helps to minimize the error in obtaining the target serum concentration of theophylline when giving a LD calculated from a predicted Vd value.     

Whole body protein turnover,studied with 15N-glycine,and muscle protein breakdown in mildly obese subjects during a protein-sparing diet and a brief total fast

A modification of the Picou and Taylor-Roberts Model was used to estimate rates of total body protein synthesis (S), breakdown (C), and amino nitrogen (N) flux (Q) in the metabolic N pool of five obese females. The subjects were fed egg white albumin at 1.5/kg ideal body weight (IBW) and total calories at 1.2 times the basal energy expenditure (fat:carbohydrate = 30%:50%) as a formula diet (period 1, 1 wk). This was followed by 3 wk during which the nonprotein calories were omitted (period 2, protein-sparing modified fast [PSMF]) and a 1-wk total fast (period 3). Estimates of body protein turnover and skeletal protein breakdown were made during the last 60 and 48 hr, respectively, of each period. Q, S, and C were 223 ± 22, 154 ± 22, and $\text{150 ± 22 g protein}\text{24 hr}$, respectively, for period 1. These values were unchanged at the end of period 2. Total fasting decreased Q and S by 36% and 27%, respectively (p < 0.001), but C remained unchanged. Skeletal protein breakdown, as estimated by urinary Nτ-methylhistidine excretion, was 108 ± 47 μmole in period 1, 79 ± 51 μmole in period 2 (p < 0.01), and 100 ± 49 μmole in period 3, representing 16 ± 5%, 12 ± 5% (p < 0.01), and 16 ± 4% of whole body breakdown. N balance was unchanged in period 1 (?0.4 ± 1.2 g N) and the final week of period 2 (?0.4 ± 1.5 g N), but was ?5.8 ± 0.6 g N in period 3. These data indicate that weight reduction with a PSMF is associated with a maintenance of total body protein turnover parameters and N balance but a reduction in skeletal protein breakdown, whereas a total fast causes a marked reduction in whole body protein synthesis and amino N flux with little change in the rate of total body and skeletal protein breakdown, resulting in a negative N balance. The minimization of N losses that develops after prolonged starvation is achieved at rates of whole body and skeletal protein breakdown similar to those found when the diet is adequate, suggesting that endogenous fat-derived fuels are as effective as exogenous energy in limiting protein catabolism. However, protein intake is necessary to maintain whole body protein synthesis under these conditions.     

Favorable effects of hydralazine on the hemodynamic response to isometric exercise in chronic severe aortic regurgitation

The hemodynamic effects of isometric exercise and the response to hydralazine therapy were evaluated in 11 patients with chronic, severe aortic regurgitation (AR). Isometric exercise produced a significant increase in heart rate (from 78 ± 11 to 93 ± 19 beats/min [mean ± standard deviation], p < 0.05), mean blood pressure (from 83 ± 8 to 104 ± 20 mm Hg, p < 0.05), mean right atrial pressure (from 3 ± 2 to 7 ± 5 mm Hg, p < 0.05) and mean pulmonary artery wedge pressure (from 12 ± 7 to 18 ± 10 mm Hg, p < 0.05). Small and insignificant changes were seen in cardiac index (from 3.4 ± 0.8 to 3.9 ± 1.0 liters/min/m²), systemic vascular resistance (from 1,097 ± 257 to 1,171 ± 284 dynes s cm^?5), pulmonary vascular resistance (from 120 ± 76 to 130 ± 89 dynes s cm^?5) and stroke volume index (from 44 ± 10 to 43 ± 12 ml/m²). After oral hydralazine administration (100 to 300 mg), hemodynamic values during isometric exercise were: Heart rate increased further, to 105 ± 14 beats/min (p < 0.05), mean blood pressure was 102 ± 16 mm Hg (difference not significant [NS]) cardiac index increased markedly, to 5.2 ± 1.4 liters/min/m² (p < 0.05), stroke volume index increased to 49 ± 12 ml/m² (p < 0.05), right atrial pressure decreased slightly, to 5 ± 5 mm Hg (NS), pulmonary artery wedge pressure decreased to 14 ± 7 mm Hg (p < 0.05), systemic vascular resistance decreased to 903 ± 288 dynes s cm^?5 (p < 0.05), and pulmonary vascular resistance changed to 100 ± 66 dynes s crrr^?5 (NS). Thus, isometric exercise in patients with chronic severe AR is associated with only a slight and insignificant increase in systemic vascular resistance, but a marked increase in pulmonary artery wedge pressure. Direct arteriolar vasodilation with hydralazine results in a significant attenuation of pulmonary artery wedge pressure increase during isometric exercise and leads concomitantly to a significant augmentation of stroke volume and cardiac output. These findings substantiate the value of hydralazine therapy in patients with chronic, severe AR.