The relative impacts of regional and generalized adiposity on insulin sensitivity have not been fully defined. Therefore, we investigated the relationship of insulin sensitivity (measured using hyperinsulinemic, euglycemic clamp technique with [3-3H] glucose turnover) to total body adiposity (determined by hydrodensitometry) and regional adiposity. The latter was assessed by determining subcutaneous abdominal, intraperitoneal, and retroperitoneal fat masses (using magnetic resonance imaging) and the sum of truncal and peripheral skinfold thicknesses. 39 healthy middle-aged men with a wide range of adiposity were studied. Overall, the intraperitoneal and retroperitoneal fat constituted only 11 and 7% of the total body fat. Glucose disposal rate (Rd) and residual hepatic glucose output (rHGO) values during the 40 mU/m2.min insulin infusion correlated significantly with total body fat (r = -0.61 and 0.50, respectively), subcutaneous abdominal fat (r = -0.62 and 0.50, respectively), sum of truncal skinfold thickness (r = -0.72 and 0.57, respectively), and intraperitoneal fat (r = -0.51 and 0.44, respectively) but not to retroperitoneal fat. After adjusting for total body fat, the Rd and rHGO values showed the highest correlation with the sum of truncal skinfold thickness (partial r = -0.40 and 0.33, respectively). We conclude that subcutaneous truncal fat plays a major role in obesity-related insulin resistance in men, whereas intraperitoneal fat and retroperitoneal fat have a lesser role. (J. Clin. Invest. 1995. 96:88-98.)

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The autosomal dominant mutation in the human alphaB-crystallin gene inducing a R120G amino acid exchange causes a multisystem, protein aggregation disease including cardiomyopathy. The pathogenesis of cardiomyopathy in this mutant (hR120GCryAB) is poorly understood. Here, we show that transgenic mice overexpressing cardiac-specific hR120GCryAB recapitulate the cardiomyopathy in humans and find that the mice are under reductive stress. The myopathic hearts show an increased recycling of oxidized glutathione (GSSG) to reduced glutathione (GSH), which is due to the augmented expression and enzymatic activities of glucose-6-phosphate dehydrogenase (G6PD), glutathione reductase, and glutathione peroxidase. The intercross of hR120GCryAB cardiomyopathic animals with mice with reduced G6PD levels rescues the progeny from cardiac hypertrophy and protein aggregation. These findings demonstrate that dysregulation of G6PD activity is necessary and sufficient for maladaptive reductive stress and suggest a novel therapeutic target for abrogating R120GCryAB cardiomyopathy and heart failure in humans.

Background —Tumor necrosis factor-α (TNF-α) is a multifunctional cytokine that has been detected in several human cardiac-related conditions, including congestive heart failure and septic cardiomyopathy. In these conditions, the origin of TNF-α secretion is, at least in part, cardiac myocytes. Methods and Results —To determine the consequences of TNF-α production by cardiac myocytes in vivo, we developed transgenic mice in which expression of a murine TNF-α coding sequence was driven by the murine α-myosin heavy chain promoter. Four transgenic founders developed an identical illness consisting of tachypnea, decreased activity, and hunched posture. In vivo, ECG-gated MRI of symptomatic transgenic mice documented a severe impairment of cardiac function evidenced by biventricular dilatation and depressed ejection fractions. All transgenic mice died prematurely. Pathological examination of affected animals revealed a globular dilated heart, bilateral pleural effusions, myocyte apoptosis, and transmural myocarditis in both the right and left ventricular free walls, septum, and atrial chambers. In all terminally ill animals, there was significant biventricular fibrosis and atrial thrombosis. Conclusions —This is the first report detailing the effects of tissue-specific production of TNF-α by cardiac myocytes in vivo. These findings indicate that production of TNF-α by cardiac myocytes is sufficient to cause severe cardiac disease and support a causal role for this cytokine in the pathogenesis of human cardiac disease.

Body fat distribution has some influence on risk factors beyond total body fat content. Both waist circumference and BMI significantly predicted risk factors after adjustment for total body fat, and for clinical purposes, most of the predictive power for men was contained in waist circumference, whereas for women, BMI and waist circumference were similarly predictive. Finally, even though the correlations between combined body fat parameters and risk factors explained only a portion of the variation in the latter, the average number of categorical metabolic risk factors increased progressively with increasing obesity. Hence, obesity seemingly has more clinical impact than revealed in these correlative studies.

Abstract-Although recent studies have suggested that blacks compared with whites have an increased prevalence of left ventricular hypertrophy, it remains uncertain whether this is true despite adjustment for body composition (fat mass and fat-free mass) and when assessed by cardiac MRI in the general population. The Dallas Heart Study is a population-based study of Dallas County in which 1335 black and 858 white participants 30 to 67 years of age underwent detailed assessment including dual-energy x-ray absorptiometry scan to measure body composition and cardiac MRI. Left ventricular hypertrophy, whether defined by indexation to body surface area (PϽ0.001), fat-free mass (Pϭ0.002), or height 2.7 (PϽ0.001) was 2-to 3-fold more common in black versus white women. Similar results were seen when comparing black and white men (PϽ0.001 when left ventricular hypertrophy was indexed to body surface area or height 2.7 and Pϭ0.05 when indexed to fat-free mass). Ethnic disparities in left ventricular mass persisted in multivariable models despite adjustment for fat mass, fat-free mass, systolic blood pressure, age, gender, and measures of socioeconomic status. We conclude that blacks compared with whites have increased left ventricular mass and a 2-to 3-fold higher prevalence of left ventricular hypertrophy in the general population, as assessed by cardiac MRI. The ethnic differences in left ventricular mass are independent of differences in body composition.

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Background It is unclear whether, and to what extent, the striking cardiac morphological manifestations of endurance athletes are a result of exercise training or a genetically determined characteristic of talented athletes. We hypothesized that prolonged and intensive endurance training in previously sedentary healthy young individuals could induce cardiac remodeling similar to that observed cross-sectionally in elite endurance athletes. Methods and Results Twelve previously sedentary subjects (aged 29±6 years; 7 men and 5 women) trained progressively and intensively for 12 months such that they could compete in a marathon. Magnetic resonance images for assessment of right and left ventricular mass and volumes were obtained at baseline and after 3, 6, 9, and 12 months of training. Maximum oxygen uptake (V̇o2 max) and cardiac output at rest and during exercise (C2H2 rebreathing) were measured at the same time periods. Pulmonary artery catheterization was performed before and after 1 year of training, and pressure-volume and Starling curves were constructed during decreases (lower body negative pressure) and increases (saline infusion) in cardiac volume. Mean V̇o2 max rose from 40.3±1.6 to 48.7±2.5 mL/kg per minute after 1 year (P<0.00001), associated with an increase in both maximal cardiac output and stroke volume. Left and right ventricular mass increased progressively with training duration and intensity and reached levels similar to those observed in elite endurance athletes. In contrast, left ventricular volume did not change significantly until 6 months of training, although right ventricular volume increased progressively from the outset; Starling and pressure-volume curves approached but did not match those of elite athletes. Conclusions One year of prolonged and intensive endurance training leads to cardiac morphological adaptations in previously sedentary young subjects similar to those observed in elite endurance athletes; however, it is not sufficient to achieve similar levels of cardiac compliance and performance. Contrary to conventional thinking, the left ventricle responds to exercise with initial concentric but not eccentric remodeling during the first 6 to 9 months after commencement of endurance training depending on the duration and intensity of exercise. Thereafter, the left ventricle dilates and restores the baseline mass-to-volume ratio. In contrast, the right ventricle responds to endurance training with eccentric remodeling at all levels of training.