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To determine the gender-specific effects of obesity on myocardial metabolism, work, and efficiency
Myocardial metabolism abnormalities may contribute to the development of obesity-related heart failure. Increased myocardial oxygen consumption (MVO2) and fatty acid (FA) metabolism and decreased efficiency occur with obesity in women. It is unknown whether similar changes occur with obesity in men.
We quantified cardiac work, and efficiency, myocardial blood flow (MBF), MVO2, glucose, and FA metabolism, with echocardiography and positron emission tomography in nonobese and obese men and women (N=86).
There were significant differences between the obese (N=35) and nonobese (N=51) in age, body composition, plasma lipids, and insulin resistance and differences between the men (N=30) and women (N=56) in body composition and plasma lipids. Female gender independently predicted increased cardiac work (p<.001). Female gender also related to lower efficiency (p<.05). Obesity and female gender independently predicted higher MBF (p<.01, p<.0005, respectively) and MVO2 (p<.0005, p<.0001). Myocardial glucose uptake was not different among the 4 subject groups, but obesity and gender interacted in predicting glucose uptake (p<.05). Lower myocardial glucose utilization was independently predicted by female gender (p<.05), and it independently predicted lower myocardial glucose utilization/plasma insulin (p<.05). Obesity and gender significantly interacted in the determination of glucose utilization/plasma insulin (p=.01). There were no differences in FA uptake among the 4 groups, and although increasing obesity correlated with higher myocardial FA utilization and oxidation; female gender (p<.005, <.01) and plasma triglycerides (p<.05, <.005) were their independent predictors.
Women’s and men’s myocardial metabolic response to obesity is not exactly the same. Obesity and gender modulate MBF and MVO2, 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.
Obesity is an independent risk factor for heart failure and is thought to contribute to 11% of heart failure cases among men and 14% among women - alarming percentages given the recent increase in obesity prevalence (1). Obesity-associated heart failure’s etiology is not completely understood. There is an increase in plasma volume, neurohormonal activation, and hemodynamic load (2). However, there are also intrinsic changes to the human myocardium that are load-independent (3).
One of these changes appears to be an alteration in myocardial metabolism. Because of the inherent link between myocardial substrate metabolism for generation of energy for cardiac function and because increased myocardial fatty acid (FA) metabolism and/or storage detrimentally affects cardiac function in animal models of obesity, we recently investigated obesity’s effects on myocardial metabolism in young women (4,5). We showed that myocardial oxygen consumption (MVO2) directly correlated with increased body mass index (BMI), and increases in myocardial FA utilization, and oxidation were predicted by increasing insulin resistance in these women (5).
There are no data, however, comparing the effects of obesity on myocardial metabolism in men and women. Epidemiologic data suggest gender-related differences in the heart’s response to obesity (1). Also, results of studies performed only in men with impaired glucose tolerance and controls do not show the same myocardial FA metabolism changes found in our study of women (6,7). Furthermore, gender affects total body, muscle, hepatic, and myocardial substrate metabolism in nonobese subjects (8-10). Thus, the purpose of this study was to determine if myocardial metabolic remodeling in response to obesity differs between men and women.
In this prospective study, we evaluated young men and premenopausal women. Of the men, 11 were obese (BMI>30kg/m2) and 19 nonobese (BMI<30kg/m2); of the women, 24 were obese and 32 nonobese. None of the data were in our first study of obesity in women. All subjects underwent a screening medical history, physical exam, and phlebotomy for fasting routine chemistries, lipid panels. Obese subjects underwent 2-hr glucose tolerance tests. Subjects were excluded if they were >350 pounds, diabetic, hypertensive, smokers, non-sedentary, taking vasoactive or lipid medications, or had cardiac disease (per history, physical exam, echocardiograms, and, if indicated, rest/stress echocardiograms). The Institutional Review Board at the Washington University School of Medicine approved this study. All subjects signed informed consent.
Subjects underwent dual-energy X-ray absorptiometry (Hologic, QDR-1000/w) for body composition measurements. All positron emission tomography (PET) studies were performed on an ECAT 962 HR+ (Siemens Medical Systems, Iselin, New Jersey) at 08:00 AM to avoid circadian variations. Subjects were admitted to the General Clinical Research Center at Washington University and were given a standardized meal the night before the PET study and then fasted for 12 hours before PET imaging. Subjects were on telemetry and had blood pressure measurement throughout the study.
Subjects underwent placement and transmission scans (for attenuation correction). PET imaging was performed after injection of 15O-water; 11C-acetate; 1-11C-glucose and 1-11C-palmitate (10-14). Throughout the PET study, we obtained plasma substrates, insulin, and radiolabeled metabolites, required for compartmental modeling of the PET data (13,14). Blood and myocardial time-activity curves were used in conjunction with well-established kinetic models to quantify MBF, MVO2, glucose extraction fraction, and FA extraction fraction (which was further divided into the portions that entered oxidation and slow turnover pools) (15). These extraction fractions were then used in conjunction with MBF and plasma substrate levels to calculate uptake and utilization of glucose and FA, and FA oxidation (10, 15).
Plasma insulin and glucose were measured by radioimmunoassay (Millipore, Billerica, MA) and using a Cobas Mira analyzer, respectively (Roche Diagnostics, Basel, Switzerland). Free FAs and lactate in the plasma were measured using an enzymatic colorimetric method (NEFA C kit, WAKO Chemicals, Richmond, VA) and photospectrometry (Sigma Chemicals, St. Louis, MO). Insulin resistance was calculated using the homeostasis model assessment (HOMA) = (fasting insulin [μU/mL] * fasting glucose [mmol/L]/22.5).
Immediately after MVO2 measurement, subjects underwent a 2-D and Doppler echocardiographic examination for quantification of left ventricular (LV) size and function using a Sequoia-C256® (Acuson-Siemens, Mountain View, CA) or a Vivid 7 (GE Medical Systems, Horten, Norway). LV mass was determined using the area-length method. LV ejection fraction was calculated using the modified Simpson’s method. Cardiac work and efficiency were calculated as previously described (5, 10).
SAS software (SAS Institute, version 9) was used for the analyses. Data are: mean values±SD. Skewed variables (plasma triglycerides and myocardial glucose utilization/plasma insulin) were log transformed. Data comparisons between any 2 of the 4 subject sets were made using unadjusted pair-wise comparisons. Analyses involving both obesity status and gender were performed using two-factor analysis of variance. Outcome variables were: MBF, MVO2, myocardial glucose uptake, utilization, utilization/plasma insulin, myocardial FA uptake, utilization, and oxidation, cardiac work, and efficiency. Initial analyses evaluated interactions between obesity and gender. When the interaction was not significant, main effects were evaluated to assess the significance of the individual factors. In one instance there was a significant obesity by gender interaction that reflected a greater decrease in myocardial glucose utilization/plasma insulin in men than in women. Because the direction of the effect was the same in both genders, we also report a gender effect in a two factor ANOVA that does not include an interaction term. To evaluate the independent effect of potential covariates (age, mean arterial pressure, HOMA, and plasma triglycerides) that were associated with outcome measures (p<.10) and to evaluate the covariate–adjusted significance of gender and obesity, these variables were included in a stepwise analysis of covariance that produced a best set of predictors. In these multivariate models each independent variable was adjusted for all other independent variables. The relationship between plasma FAs and myocardial FA utilization or oxidation was not analyzed because plasma FAs are used in their calculation. Similarly, HOMA and myocardial glucose utilization/plasma insulin’s relationship was not analyzed. A p<.05 was considered significant.
The nonobese and obese differed in almost all clinical characteristics (Table 1). The genders differed in body composition, high-density lipoprotein and triglyceride levels (Table 1). There were racial differences between the men and women (p<.05) but no racial differences in any of the outcomes (data not shown).
The obese had higher blood pressure, heart rate, rate-pressure product, and LV mass than the nonobese (Table 2). The men had higher LV mass and lower LV mass/fat-free mass, ejection fraction, and cardiac work compared with women (Table 2). Female gender related to higher work (Table 4A lists all univariate relationships) and was its only independent predictor (Table 4B lists all multivariate model results).
Table 3 shows levels during the PET. Glucose levels were higher in the obese and in men. Lactate was higher in men. Insulin was higher in the obese.
Figure 1A depicts MBF (nonobese men, obese men, nonobese women, obese women =0.95±0.19, 0.99±0.18, 1.10±0.21, 1.29±0.30mL*g−1*min−1). Figure 1B shows MVO2 (nonobese men, obese men, nonobese women, obese women =4.1±0.8, 4.5±1.3, 5.8±1.0, 7.1±1.6mL*g−1*min−1). Gender’s and obesity’s effects on MBF and MVO2 are also demonstrated in Figures Figures2,2, ,3,3, and and4.4. Female gender and obesity independently predicted MBF and MVO2, accounting for 22 and 47% of their variability, respectively. Obesity and gender did not interact in determining MBF or MVO2 (Table 4C lists all interaction results).
Women had lower efficiency than men (Table 2), and female gender independently predicted lower efficiency (p<.05). However, if plasma triglycerides were added to the multivariate model, gender lost its significance, likely because of the relationship between gender and triglycerides (p<.005).
In exploratory analyses, we evaluated cardiac work’s effect on MVO2. Work related to MVO2 (r=.36, p<.001) but did not independently predict it, likely because of the significant relationship between gender and work. Also, given gender differences in LV mass/fat-free mass we determined that it significantly interacted with gender in the prediction of MBF, and when added to the model, obesity was no longer an independent predictor. In this model, LV mass/fat-free mass and gender accounted for 32% of the variation in MBF.
Myocardial glucose uptake was not different among the groups, and although gender and obesity were not significantly related to uptake, they significantly interacted in predicting uptake (Figure 5A; Table 4C). Myocardial glucose utilization was not different among the subjects, but female gender predicted lower glucose utilization (p<.05). Figure 5B shows myocardial glucose utilization/plasma insulin (nonobese men, obese men, nonobese women, obese women =90±64, 17±23, 45±43, 25±25[nmol*g−1*min−1]/[μU*mL−1]. It related inversely to obesity and plasma triglycerides but not gender. However, in the multivariate analysis female gender (p<.05) and plasma triglycerides (p<.01) predicted lower myocardial glucose utilization/insulin, accounting for 32% of its variability. Obesity and gender interacted in predicting myocardial glucose utilization/insulin (Figure 5B; Table 4C).
There were no differences in myocardial FA uptake among the 4 groups. However, female gender predicted increased FA uptake (p<.05). Myocardial FA utilization (nonobese men, obese men, nonobese women, obese women =111±48, 149±41, 142±50, 169±40nmol*g−1*min−1), related to obesity, female gender, age, plasma triglyceride levels, and mean arterial pressure (Table 4A). However, only female gender and triglyceride levels independently predicted increased FA utilization, accouting for 27% of its variability. Myocardial FA oxidation (nonobese men, obese men, nonobese women, obese women = 101±44, 140±41, 122±43, 156±40nmol*g−1*min−1) related to obesity, female gender, age, plasma triglycerides, and mean arterial pressure, but only plasma triglycerides and gender independently predicted it, accouting for 31% of its variability.
Our results are the first to demonstrate different myocardial metabolic signatures in men and women in response to obesity. Specifically, both obesity and female gender independently predict higher MBF and MVO2. Female gender independently predicts higher cardiac work, lower myocardial glucose uptake, utilization, and utilization/plasma insulin. Moreover, obesity and gender interact in determining myocardial glucose uptake and insulin sensitivity, which highlights the complexity of their relationship on influencing myocardial metabolism. Although obesity and myocardial FA metabolism correlate, female gender independently predicts higher FA metabolism, and female gender relates to inefficiency (Of note, multivariate analyses using the continuous variable, BMI, instead of obese/nonobese did not alter any of our results, data not shown).
Our finding that both obesity and gender affect MBF helps explain the apparently conflicting results of studies regarding obesity and MBF. In our study of women, obesity predicted MBF but in another study of men, obesity did not (5,16). The interaction between gender and LV mass/fat-free mass also affects MBF. Differences in MBF with obesity likely involve a complex interaction between vasodilatory and constrictive influences, including sex hormones, genomic differences, hormone receptors, and metabolites, as evidenced by the fact that men and women’s vasoactive responses to sex hormones are not the same (17,18).
The increase in MVO2 with obesity and female gender extends our previous findings showing increasing MVO2 with increasing obesity in women (5). Cardiac work influences MVO2 but was not an independent predictor. (Work’s significant relationship with female gender further underscores the complexity of the influences on MVO2). The increased MVO2 seen in women and the obese may be in part because increased myocardial FA oxidation related to female gender and obesity since FA oxidation is less oxygen efficient than glucose oxidation. The borderline higher plasma FA levels in the obese and in the women may also increase MVO2 via upregulation of uncoupling proteins; higher estrogen levels in women may also increase MVO2 via upregulation of uncoupling proteins and their function (19,20). Upregulation of uncoupling proteins uncouples oxygen consumption from ATP production (for cardiac work), hence, they may also play a role in the lower efficiency seen in the women.
Concordant with our previous results in women, obesity at first glance appears to have little effect on glucose metabolism (5). However, with obesity, and increasing whole body insulin resistance, the myocardium utilizes less glucose/plasma insulin and thus appears insulin resistant. Furthermore, obesity and gender interact significantly in the prediction of glucose uptake and glucose utilization/insulin, and female gender is an independent predictor of lower glucose utilization/plasma insulin. Female gender also predicts less myocardial glucose utilization. Estrogen may be involved in this lower glucose uptake and utilization, as it decreases glucose oxidation, gluconeogenesis, and glycogenolysis in other organs, and reduces glucose transporter 4 translocation to the cell surface, thereby inhibiting glucose uptake (21-23). Female gender also may decrease glucose metabolism via the Randle cycle due to women’s higher whole body FA turnover, delivery to the myocardium, and myocardial FA oxidation (22).
Our results also clarify apparently conflicting results from previous myocardial FA metabolism studies in obese humans: those in women demonstrated increased FA metabolism while those in men did not (5,6,24). Our current study demonstrates that while both obesity and gender are related to myocardial FA metabolism, gender is the stronger predictor and so must be taken into account when determining obesity’s effect. The relationship between plasma triglycerides and obesity may also have caused that between obesity and the measures of FA metabolism to be less significant in multivariate models. The increase in myocardial FA metabolism seen with obesity is likely secondary to increased presentation of plasma FA to the myocardium, resulting from obesity’s known increase in whole body FA turnover. Additionally, estrogen increases lipoprotein lipase’s and FA oxidation enzymes’ activity and so may partly explain the increase in myocardial FA metabolism in women (25,26).
Our findings may not apply to subjects who do not fit our entry criteria. This study was not powered to evaluate the effect of sex hormones, and menstrual phase on myocardial metabolism but rather to evaluate the effects of gender and obesity and their interactions. Further studies are needed to determine if these variables are involved in the mechanism(s) effecting gender-related myocardial metabolic adaptations to obesity. We did not evaluate metabolism of endogenous substrates or other exogeous substrates (e.g., lactate) although these would be expected to contribute little to myocardial metabolism in the rested state.
Given the link between metabolism and function, changes in myocardial metabolism due to obesity may contribute to obesity-related contractile dysfunction. Increased MVO2 in obesity may contribute to decreased function via impaired efficiency of transformation of chemical energy into mechanical function. Increased FA oxidation with obesity may also lead to LV dysfunction, as seen in animal models (27). Further studies are necessary to prove that altered myocardial metabolism (accounting for gender-related differences) contributes to the development of obesity-related cardiac dysfunction.
Myocardial insulin resistance in obesity likely affects the myocardium’s ability to adapt to changing conditions. One would speculate that insulin resistant myocardium would not be able to adapt to ischemia (which requires glucose use) as well as the insulin sensitive heart. Further investigation in ischemic myocardium is needed.
Our finding of gender-related differences in the myocardial metabolic response to obesity makes it tempting to speculate that the known gender differences in risk of obesity-related cardiac dysfunction may have a causal relationship. To be certain, differences other than myocardial metabolism likely also influence cardiac dysfunction development in obesity. However, our findings suggest that further study of obesity- and gender-related myocardial metabolic changes may yield novel, gender-specific therapeutic targets for functional improvement.
The myocardial metabolic response to obesity is complex and affected by gender. Obesity and gender independently modulate MBF and MVO2. And although both modulate myocardial substrate metabolism, gender was a stronger predictor and affected efficiency. Lastly, it appears that the myocardium can become insulin resistant with obesity, and gender and obesity interact in predicting myocardial glucose uptake and insulin sensitivity.
In 86 young men and pre-menopausal women, the effects of obesity and gender on myocardial metabolism and efficiency were assessed prospectively with PET. Obesity and female gender independently predicted higher myocardial blood flow and oxygen consumption. However, despite greater cardiac work, the myocardial efficiency was less in women than in men. Female gender was an independent predictor of lower myocardial glucose utilization and glucose utilization/plasma insulin, reflecting insulin resistance. These data suggest that while the myocardium can become insulin resistant with obesity, the gender of the subject should also be taken into consideration, since female gender is a stronger and independent modulator of myocardial substrate utilization and efficiency.
We thank Jean Schaffer, MD and Kristin O’Callaghan for their critical review of this manuscript; JoAnn Marsala, RN, Kitty Krupp, RN, Scott Weber, RN, Amanda Demoss, Jeffrey Baumstark, Linda Becker, and Natasha Sullivan for technical assistance; and Ava Ysaguirre for manuscript preparation assistance.
Sources of Funding: Barnes-Jewish Hospital Foundation grant, St. Louis, MO; NIH Grants RO1-HL073120, AG15466, K23-HL077179, PO1-HL13851, RR00036, DK056341, P60-DK 020579-30, Bethesda, MD, Robert Wood Johnson Foundation grant 051893, American Heart Association AHA02255732, Princeton, NJ, USA.
Conflicts of interest: none.