Effects of human immunodeficiency virus and metabolic complications on myocardial nutrient metabolism, blood flow, and oxygen consumption: a cross-sectional analysis.

BACKGROUND: In the general population, peripheral metabolic complications (MC) increase the risk for left ventricular dysfunction. Human immunodeficiency virus infection (HIV) and combination anti-retroviral therapy (cART) are associated with MC, left ventricular dysfunction, and a higher incidence of cardiovascular events than the general population. We examined whether myocardial nutrient metabolism and left ventricular dysfunction are related to one another and worse in HIV infected men treated with cART vs. HIV-negative men with or without MC. METHODS: Prospective, cross-sectional study of myocardial glucose and fatty acid metabolism and left ventricular function in HIV+ and HIV-negative men with and without MC. Myocardial glucose utilization (GLUT), and fatty acid oxidation and utilization rates were quantified using 11C-glucose and 11C-palmitate and myocardial positron emission tomography (PET) imaging in four groups of men: 23 HIV+ men with MC+ (HIV+/MC+, 42 ± 6 yrs), 15 HIV+ men without MC (HIV+/MC-, 41 ± 6 yrs), 9 HIV-negative men with MC (HIV-/MC+, 33 ± 5 yrs), and 22 HIV-negative men without MC (HIV-/MC-, 25 ± 6 yrs). Left ventricular function parameters were quantified using echocardiography. RESULTS: Myocardial glucose utilization was similar among groups, however when normalized to fasting plasma insulin concentration (GLUT/INS) was lower (p < 0.01) in men with metabolic complications (HIV+: 9.2 ± 6.2 vs. HIV-: 10.4 ± 8.1 nmol/g/min/µU/mL) than men without metabolic complications (HIV+: 45.0 ± 33.3 vs. HIV-: 60.3 ± 53.0 nmol/g/min/µU/mL). Lower GLUT/INS was associated with lower myocardial relaxation velocity during early diastole (r = 0.39, p < 0.001). CONCLUSION: Men with metabolic complications, irrespective of HIV infection, had lower basal myocardial glucose utilization rates per unit insulin that were related to left ventricular diastolic impairments, indicating that well-controlled HIV infection is not an independent risk factor for blunted myocardial glucose utilization per unit of insulin. TRIAL REGISTRATION: NIH Clinical Trials NCT00656851.

Sex differences in myocardial oxygen and glucose metabolism.

BACKGROUND: Both physiologic and pathophysiologic conditions affect the myocardium's substrate use and, consequently, its structure, function, and adaptability. The effect of sex on myocardial oxygen, glucose, and fatty acid metabolism in humans is unknown. METHODS AND RESULTS: We studied 25 young subjects (13 women and 12 men) using positron emission tomography, quantifying myocardial blood flow, myocardial oxygen consumption (MVO2), and glucose and fatty acid extraction and metabolism. MVO2 was higher in women than in men (5.74 +/- 1.08 micromol x g(-1) x min(-1) vs 4.26 +/- 0.69 micromol x g(-1) x min(-1), P < .005). Myocardial glucose extraction fraction and utilization were lower in women than in men (0.025 +/- 0.019 vs 0.062 +/- 0.028 [P < .001] and 133 +/- 96 nmol x g(-1) x min(-1) vs 287 +/- 164 nmol x g(-1) x min(-1) [P < .01], respectively). There were no sex differences in myocardial blood flow, fatty acid metabolism, or plasma glucose, fatty acid, or insulin levels. Female sex was an independent predictor of increased MVO2 (P = .01) and decreased myocardial glucose extraction fraction and utilization (P < .005 and P < .05, respectively). Insulin sensitivity was an independent predictor of increased myocardial glucose extraction fraction and utilization (P < .01 and P = .01, respectively). CONCLUSIONS: Further studies are necessary to elucidate the mechanisms responsible for sex-associated differences in myocardial metabolism. However, the presence of such differences may provide a partial explanation for the observed sex-related differences in the prevalence and manifestation of a variety of cardiac disorders.

Impact of gender on the myocardial metabolic response to obesity.

OBJECTIVES: We sought to determine the gender-specific effects of obesity on myocardial metabolism, work, and efficiency. BACKGROUND: Myocardial metabolism abnormalities may contribute to the development of obesity-related heart failure. Increased myocardial oxygen consumption (MVO(2)) and fatty acid (FA) metabolism and decreased efficiency occur with obesity in women. It is unknown whether similar changes occur with obesity in men. METHODS: We quantified cardiac work, efficiency, myocardial blood flow (MBF), MVO(2), glucose, and FA metabolism with echocardiography and positron emission tomography in nonobese and obese men and women (N = 86). RESULTS: There were significant differences between the obese (n = 35) and nonobese (n = 51) subjects in age, body composition, plasma lipids, and insulin resistance in addition to differences between the men (n = 30) and women (n = 56) in body composition and plasma lipids. Female gender independently predicted increased cardiac work (p < 0.001). Female gender also related to lower efficiency (p < 0.05). Obesity and female gender independently predicted greater MBF (p < 0.01, p < 0.0005, respectively) and MVO(2) (p < 0.0005, p < 0.0001). Myocardial glucose uptake was not different among the 4 subject groups, but obesity and gender interacted in predicting glucose uptake (p < 0.05). Lower myocardial glucose utilization was independently predicted by female gender (p < 0.05), and it independently predicted lower myocardial glucose utilization/plasma insulin (p < 0.05). Obesity and gender significantly interacted in the determination of glucose utilization/plasma insulin (p = 0.01). There were no differences in FA uptake among the 4 groups, and although increasing obesity correlated with greater myocardial FA utilization and oxidation; female gender (p < 0.005, p < 0.01) and plasma triglycerides (p < 0.05, p < 0.005) were their independent predictors. CONCLUSIONS: Women's and men's myocardial metabolic responses to obesity are not exactly the same. Obesity and gender modulate MBF and MVO(2), are related to myocardial substrate metabolism, and sometimes interact in its prediction. Gender modifies efficiency. Gender-related differences in myocardial metabolism may affect the development of/adaptation to obesity-related cardiac disease.

Exercise training impacts the myocardial metabolism of older individuals in a gender-specific manner.

Aging is associated with decreases in aerobic capacity, cardiac function, and insulin sensitivity as well as alterations in myocardial substrate metabolism. Endurance exercise training (EET) improves cardiac function in a gender-specific manner, and EET has been shown to improve whole body glucose tolerance, but its effects on myocardial metabolism are unclear. Accordingly, we studied the effect of EET on myocardial substrate metabolism in older men and women. Twelve healthy older individuals (age: 60-75 yr; 6 men and 6 women) underwent PET with [(15)O]water, [(11)C]acetate, [(11)C]glucose, and [(11)C]palmitate for the assessment of myocardial blood flow (MBF), myocardial O(2) consumption (MVo(2)), myocardial glucose utilization (MGU), and myocardial fatty acid utilization (MFAU), respectively, at rest and during dobutamine infusion (10 microg.kg(-1).min(-1)). Measurements were repeated after 11 mo of EET. Maximal O(2) uptake (Vo(2max)) increased (P = 0.005) after EET. MBF was unaffected by training, as was resting MVo(2); however, posttraining dobutamine MVo(2) was significantly higher (P = 0.05), as was MGU (P < 0.04). Although overall dobutamine MFAU was unchanged, posttraining dobutamine MFAU increased in women (P = 0.01) but decreased in men (P = 0.03). Thus, EET in older individuals improves the catecholamine response of myocardial glucose metabolism. Moreover, gender differences exist in the myocardial fatty acid metabolic response to training. These findings suggest a role for altered myocardial substrate metabolism in modulating the cardiovascular benefits of EET in older individuals.

Metabolic syndrome is associated with abnormal left ventricular diastolic function independent of left ventricular mass.

AIM: To characterize the extent to which metabolic syndrome criteria predict left ventricular (LV) structure and function. METHODS AND RESULTS: Metabolic syndrome criteria were assessed in 607 adults with normal LV function. The cohort was grouped according to the number of criteria satisfied: (1) Absent (0 criteria, n = 110); (2) Pre-Metabolic Syndrome (1-2 criteria, n = 311); and (3) Metabolic Syndrome (>or=3 criteria, n = 186). Echocardiography was used to assess LV structure (LV mass) and systolic (LVEF, Vs) and diastolic function, by pulse-wave Doppler (E/A ratio) and tissue Doppler imaging (Ve). LV volumes and LVEF were similar between groups. However, LV mass increased significantly and progressively (LVM/Ht(2.7), in g/m(2.7): 34.9 +/- 6.7, 41.0 +/- 9.5, 46.3 +/- 11.0, P < 0.001); LV relaxation decreased progressively (Ve(global'), in cm/s: 13.5 +/- 2.8, 12.1 +/- 3.0, 10.5 +/- 2.2, P < 0.001) from Absent to Pre-Metabolic Syndrome to Metabolic Syndrome groups, respectively. Multiple variable analyses showed that diastolic blood pressure, waist circumference, and triglyceride levels were independent predictors of Ve after adjustment for LV mass. CONCLUSION: Patients with metabolic syndrome have LV diastolic dysfunction independent of LV mass. These functional abnormalities may partially explain the increased cardiovascular morbidity and mortality associated with metabolic syndrome.

Hypertensive left ventricular hypertrophy is associated with abnormal myocardial fatty acid metabolism and myocardial efficiency.

BACKGROUND: Hypertension-induced left ventricular hypertrophy (LVH) is associated with an increased risk of cardiovascular morbidity and death by mechanisms not well characterized. METHODS AND RESULTS: Myocardial fatty acid (FA) metabolism and left ventricular (LV) mass were evaluated in 13 patients with hypertensive LVH with normal LV ejection fraction and 42 normal control subjects (primary cohort). Contractile performance was also evaluated in 5 hypertensive LVH patients and 5 matched normal control subjects (magnetic resonance [MR] substudy). Myocardial FA utilization (MFAU) and myocardial FA oxidation (MFAO) were assessed by positron emission tomography by use of 1-carbon-11 palmitate. Myocardial contractile function (strain and stress) was determined by cardiac MR imaging with tissue tagging and calibrated arterial pressure traces; myocardial external minute work and efficiency were derived. In the primary cohort decreased MFAO was predictive of increased LV mass (model r(2) = 0.61, P = .03). In the MR substudy decreased MFAO (corrected for myocardial oxygen consumption [MVO(2)]) in the hypertensive LVH group compared with the normal group (MFAU/MVO(2), 26 +/- 5 vs 37 +/- 8; MFAO/MVO(2), 24 +/- 6 vs 35 +/- 7; both P = .03) was paralleled by decreased myocardial external minute work (0.13 +/- 0.03 J x g(-1) x min(-1) vs 0.17 +/- 0.04 J x g(-1) x min(-1), P = .07) and decreased myocardial efficiency (5.2% +/- 1.4% vs 7.1% +/- 1.0%, P = .03). CONCLUSIONS: Abnormalities in myocardial FA metabolism are apparent in hypertensive LVH, and these abnormalities may be responsible, at least in part, for a reduction in myocardial efficiency.

Impact of hormone replacement on myocardial fatty acid metabolism: potential role of estrogen.

BACKGROUND: Estrogen increases fatty acid utilization and oxidation and may decrease glucose use in human skeletal muscle, whereas these effects are attenuated by progesterone. Whether these ovarian hormones exhibit similar effects on myocardial metabolism is unknown. METHODS AND RESULTS: Myocardial blood flow and oxygen consumption, as well as glucose and fatty acid metabolism, were examined retrospectively by use of positron emission tomography in 24 postmenopausal women receiving estrogen (n = 7), estrogen plus progesterone (n = 8), or no hormone replacement (n = 9) and in 22 age-matched men. Myocardial blood flow was higher in women regardless of hormone replacement status. Myocardial oxygen consumption was higher in women taking estrogen only when compared with men (7.3 +/- 1.6 micromol.g(-1).min(-1) vs 4.6 +/- 1.2 micromol.g(-1).min(-1), P < .001). Glucose utilization was not affected by gender or hormone replacement. Whereas fatty acid levels and the degree of myocardial fatty acid uptake were not distinguished by gender or hormone use, myocardial fatty acid utilization was higher in women taking estrogen when compared with men (259 +/- 68 nmol.g(-1).min(-1) vs 176 +/- 50 nmol.g(-1).min(-1), P = .01) and trended higher when compared with women not receiving hormonal therapy (185 +/- 46 nmol.g(-1).min(-1), P = .07) but was not different from that of women taking estrogen plus progesterone (205 +/- 58 nmol.g(-1).min(-1), P = not significant). CONCLUSIONS: In postmenopausal women, estrogen use is associated with increased myocardial fatty acid utilization. Thus, when the cardiac effects of hormone replacement therapy are being assessed, alterations in myocardial substrate metabolism should be considered.

Impact of aging on myocardial metabolic response to dobutamine.

In humans, under resting conditions there is an age-related decrease in myocardial fatty acid utilization (MFAU) and oxidation (MFAO) and a relative increase in myocardial glucose utilization (MGU). The impact of age on an individual's myocardial metabolic response to catecholamines is not well defined. Sixteen younger (mean age, 26 +/- 5 yr) and 14 older (mean age, 69 +/- 4 yr) volunteers underwent positron emission tomography to measure myocardial blood flow, myocardial oxygen consumption (M.VO2), MFAU, MFAO, and MGU both under resting conditions and during dobutamine infusion. In response to dobutamine administration, the rate-pressure product, myocardial blood flow, and M.VO2 measurements increased by similar amounts in both groups. No age-related differences were noted in the responses of plasma insulin, glucose, fatty acid, or lactate levels to dobutamine. With dobutamine infusion, MFAU and MFAO increased by a similar extent in both younger and older volunteers (age/dobutamine interactions, P = 0.62 and 0.75, respectively). In contrast, MGU increased with dobutamine administration in the younger (from 149 +/- 71 to 209 +/- 78 nmol.g(-1).min(-1); P = 0.04) but not in the older (from 235 +/- 147 to 176 +/- 84 nmol.g(-1).min(-1); P = 0.23; age/dobutamine interaction, P = 0.03) group. With dobutamine infusion, hearts in both younger and older volunteers responded by increasing their MFAU and MFAO values. Whereas younger hearts also responded with an increase in MGU, older hearts did not. Although the clinical significance of these findings awaits further study, these results may partially explain the impaired contractile reserve and the increased incidence of cardiovascular disease in older individuals.