Changes in endothelial function and depression scores are associated following long-term dietary intervention: A secondary analysis

Nutrition 29 (2013) 1271–1274

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Changes in endothelial function and depression scores are associated following long-term dietary intervention: A secondary analysis Lisa J. Moran Ph.D. a, *, Carlene J. Wilson Ph.D. b, Jonathan D. Buckley Ph.D. c, Manny Noakes Ph.D. d, Peter M. Clifton Ph.D. e, Grant D. Brinkworth Ph.D. d a

The Robinson Institute, Discipline of Obstetrics and Gynaecology, University of Adelaide; South Australian Health and Medical Research Institute, Adelaide, Australia Discipline of Public Health, Flinders University of South Australia, Adelaide, Australia Nutritional Physiology Research Centre, Sansom Institute for Health Research, University of South Australia, Adelaide, Australia d CSIRO Preventative Health Flagship and CSIRO Animal, Food and Health Sciences, Adelaide, Australia e School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, Australia b c

a r t i c l e i n f o

a b s t r a c t

Article history: Received 26 February 2013 Accepted 26 March 2013

Objective: Cross-sectional studies show associations between depression and endothelial function (as measured by endothelium-dependent brachial artery flow-mediated dilatation [FMD]); but it is not known whether changes in these parameters are associated following dietary management. We have previously reported that compared with consumption of a high-carbohydrate (HC) diet, despite comparable weight loss, a very low-carbohydrate (LC diet) impaired FMD and increased depression. The purpose of this study was to conduct a secondary analysis to examine whether there was an association between changes in FMD and depression. Methods: Forty-seven overweight men and women (body mass index 26–43 kg/m2 and ages 24–64 y) completed a 12-mo randomized controlled trial during which participants consumed either an energy-restricted, isocaloric LC or HC diet. Weight, body composition, Homeostasis Assessment of Insulin Resistance (HOMA), depression (Beck Depression Inventory [BDI]), Anxiety (Spielberger State-Trait Anxiety Inventory [STAI]) and FMD were assessed before and after the intervention. This secondary analysis focused on multiple regression analysis of these parameters. Results: Changes in BDI were independently predicted by changes in FMD (b ¼ 0.356; P ¼ 0.026) but not by diet intervention assignment or changes in weight or HOMA. No variables were significant predictors of the change in STAI. Conclusions: Over time, impairments in FMD were independently associated with increased depression, independent of diet composition, or changes in weight and insulin resistance. This data supports a mechanistic association between depression and endothelial function, which may influence long-term health. Ó 2013 Elsevier Inc. All rights reserved.

Keywords: Depression Endothelial function Diet

Introduction The obesity epidemic has led to widespread interest in alternative dietary compositions, including very lowcarbohydrate (LC), high-fat diets, as a weight loss strategy [1]. LJM and GDB had full access to all of the data in the study and take reasonability for the integrity of the data and the accuracy of the data analysis. Study conception and design and analysis and interpretation of data: LJM, CJW, JDB, MN, PMC, GDB; Acquisition of data: GDB and CJW; Drafting of the manuscript: LJM and GDB; Critical revision of the manuscript for important intellectual content: CJW, JDB, MN and PMC; Obtained funding: GDB, JDB, MN, PMC, and CJW; and Study supervision: GDB. The authors have nothing to disclose. * Corresponding author. Tel.: þ61 08 8313 1352; fax: þ61 08 8313 1355. E-mail address: [email protected] (L. J. Moran). 0899-9007/$ - see front matter Ó 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.nut.2013.03.023

We recently conducted a 12-mo study comparing the effects of an energy-restricted LC diet with an isocaloric highcarbohydrate (HC) diet [2–4]. This study showed that after 8 wk, participants in both diet groups had comparable weight loss and reductions in depression and anxiety; however, over the long-term (weeks 8 to 52), despite comparable levels of weight loss in both groups, the depression and anxiety scores were maintained for the HC diet at the lower and improved level, but scores returned to more negative baseline levels for the LC diet [3]. This suggests that some aspect/s of the LC diet may have detrimental effects on psychological functions that negate the positive effects of the long-term weight loss observed with the HC diet. However, the exact mechanism for this potential association remains unknown. The same trial also revealed that over

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the long-term (52 wk), consumption of an LC diet impaired flow-mediated dilatation (FMD; a marker of endothelial function) with no change in FMD for the HC diet [2]. A separate body of evidence indicates the existence of a relationship between psychological function and cardiovascular disease (CVD), with depression and/or anxiety associated with coronary artery disease (CAD) [5,6]. Recent evidence from a meta-analysis (N ¼ 12 studies, N ¼ 1491 participants) suggests this may be mediated through endothelial dysfunction at an early stage of atherosclerosis contributing to depression, supported by an inverse association between depression and FMD [7]. However, depression treatment improved FMD in patients with depression and established CAD [8], suggesting that rather than FMD effecting depression it may be that depression has an adverse effect on FMD. Collectively, this evidence suggests our prior observations of an LC diet impairing FMD and negating improvements in psychological function associated with weight loss with an HC diet, may be interrelated. Therefore, the aim of this study was to conduct a secondary analysis in the same cohort to examine the association between changes in FMD and psychological function following long-term consumption of either an LC or an HC diet.

Table 1 Baseline characteristics

Methods

HOMA. Two-tailed analysis was performed using SPSS 19.0 (SPSS Inc., Chicago) with statistical significance at P < 0.05.

Men/Women Weight (kg) BMI (kg/m2) Glucose (mmol/L) Insulin (mU/L)* HOMA* TC (mmol/L) LDL-C (mmol/L) HDL-C (mmol/L) Triglycerides (mmol/L)* C-reactive protein (mg/L) Systolic blood pressure Diastolic blood pressure Flow-mediated dilatation (%) State Trait Anxiety Index Beck Depression Inventory

LC

HC

7/18 93.5 33.5 5.6 8.3 2.1 5.6 3.4 1.4 1.7 4.6 134.1 73.4 5.8 31.1 5.5

8/14 97.2 34.0 5.5 9.9 2.5 5.6 3.4 1.4 1.8 5.8 136.9 78.3 5.8 33.3 6.5

              

16.2 4.3 0.4 3.5 0.9 0.9 1.0 0.3 0.7 5.4 15.6 13.0 3.7 8.4 4.8

              

13.1 4.0 0.6 4.0 1.3 0.8 0.7 0.3 0.9 4.8 13.5 12.1 2.6 11.0 7.5

ANOVA, analysis of variance; BMI, body mass index; HC, high-carbohydrate diet; HDL-C, high-density lipoprotein cholesterol; HOMA, Homeostasis Model Assessment of Insulin Resistance; LC, very low-carbohydrate diet; LDL-C, lowdensity lipoprotein cholesterol; TC, total cholesterol Data are means  SD * Log-transformed data.

Participants and design The participants, study design, and inclusion and exclusion criteria have been previously reported [2,3]. The study was approved by the Human Research Ethics Committees of the Commonwealth Scientific and Industrial Research Organisation and the University of South Australia, Adelaide. All participants provided written informed consent. In summary, 122 overweight and obese (body mass index [BMI] 26–43 kg/m2) participants were recruited with 118 randomized to the consumption of either an energy-restricted (w 6000 kcal/d for women and w 7000 kcal/d for men) LC or isocaloric HC diet for 52 wk [4]. Fasting weight, height, BMI, insulin, glucose, insulin resistance (assessed using Homeostasis Model Assessment [HOMA] ¼ fasting insulin [mU/L]  glucose [mmol/L]/22.5), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglycerides, C-reactive protein (CRP), blood pressure (BP), endothelium-dependent brachial artery FMD, Beck Depression Inventory (BDI), and Spielberger State-Trait Anxiety Inventory (STAI) were assessed at weeks 0, 8, and 52 [2–4]. It has been previously reported that overall, both diet groups had comparable reductions in weight, BMI, glucose, insulin, HOMA, CRP, and BP [2,4]; although compared with the HC diet group the LC group had greater increases in TC, LDL-C, and HDL-C and greater reductions in triglycerides and FMD [2,4]. It also has been previously reported that although both dietary interventions had similar initial improvements in mood (specifically reductions in BDI and STAI) after 8 wk, these improvements were not sustained over 12 mo with the LC diet, with scores returning to negative baseline levels compared with the HC diet [4]. Hence, because the differential dietary-related psychological responses were only observed during this latter period, only data between weeks 8 and 52 and corresponding changes were selected for this secondary analysis that comprised participants who completed the study with available psychological and FMD data (LC ¼ 25, HC ¼ 22). Baseline characteristics of this group are described in Table 1. One participant in each diet group reported antidepressant or antianxiety medication changes over the study and analyses of psychological outcomes were conducted with and without these participants included.

Results Overall, changes in FMD were inversely correlated with the change in BDI (r ¼ 0.361; P ¼ 0.016), indicating a decrease in FMD was associated with an increase in depression score (Fig. 1). No other variables were associated with changes in FMD, BDI, or STAI. Multiple regression analysis revealed the change in BDI was independently predicted by the change in FMD (b ¼ 0.356; P ¼ 0.026). No variables were significant predictors of the change in STAI (Table 2). These relationships were maintained after removing the two participants who modified their psychological medication during the study. Discussion This study showed a significant independent association between the change in depression and the change in FMD in

Statistics Because the changes in the outcome parameters just summarized have been reported in detail elsewhere, these results are not duplicated here. The purpose of this contribution was to determine the association between the changes in these variables and specifically the association between the changes in depression and FMD. Data are expressed as mean  SD and were log-transformed before analysis where data were skewed. The relationships between variables were examined using bivariate correlations or multiple linear regressions. The independent variables were selected for each regression model based on hypothesis testing or associations on correlations (with a P-value < 0.2 considered for inclusion). Multiple linear regression models were constructed to assess independent predictors of the change in BDI or STAI with the final models containing diet intervention assignment, change in FMD, change in weight, and change in

Fig. 1. Correlation between the change in depression and flow-mediated dilation following either a very low-carbohydrate diet or a high-carbohydrate diet. Data were analyzed by bivariate correlation.

L. J. Moran et al. / Nutrition 29 (2013) 1271–1274 Table 2 Multiple linear regression assessing independent predictors of the change in depression or anxiety following either a very low-carbohydrate diet or a highcarbohydrate diet

Change in FMD (%) Change in weight (kg) Change in HOMA Diet intervention allocation Overall model

Change in BDI

Change in STAI

b ¼ 0.356; P ¼ 0.026 b ¼ 0.055; P ¼ 0.724 b ¼ 0.058; P ¼ 0.705 b ¼ 0.004; P ¼ 0.984

b ¼ 0.115; P ¼ 0.480 b ¼ 0.051; P ¼ 0.756 b ¼ 0.068; P ¼ 0.674 b ¼ 0.100; P ¼ 0.550

r2 ¼ 0.049; P ¼ 0.205

r2 ¼ 0.060; P ¼ 0.813

BDI, Beck Depression Inventory; FMD, flow-mediated dilation; HOMA, Homeostasis Model Assessment of Insulin Resistance; STAI, Spielberger State-Trait Anxiety Inventory Data were analyzed by multiple linear regression

overweight and obese men and women following an LC or an HC weight loss diet. Specifically, impairments in FMD were independently associated with increases in depression. This secondary analysis provides additional insight and explanation for our previous observation in this study of the negated mood improvement with weight loss following long-term consumption of an LC diet [4] because the LC diet also reduced FMD [2]. However, from the current data, causality of the observed relationship cannot be determined. Whether the poorer mood response with the LC diet promoted a decrease in FMD or that the decrease in FMD that occurred with the LC diet counteracted any weight loss induced improvement in mood remains unclear. The relationship observed between the change in depression and FMD is consistent with prior cross-sectional associations between depression and FMD [7] or CAD [5,6]. Case–control studies have also shown that coronary endothelial function and brachial artery FMD is impaired in patients with depression compared with non-depressive controls [9,10]. The potential underlying mechanisms for these associations include depression-induced alterations in the hypothalamic–pituitary axis, autonomic or immune function resulting in elevated proinflammatory cytokines [11]. This is supported by elevated inflammatory markers including CRP, interleukin (IL)-6, IL-1b, IL-2, IL-8, IL-12 and tumor necrosis factor-a in depression [12]. Furthermore, treatment of depression with selective serotonin reuptake inhibitors improves FMD in association with CRP and IL-6 in patients with depression and established CAD [8]. This collectively suggests a causative relationship between depression, FMD and CVD with depression promoting endothelial dysfunction. Alternatively, depression may occur as a result of developing metabolic diseases due to the diagnosis of a chronic disease or the existence of deleterious lifestyle factors. This also may reflect the effect of peripheral proinflammatory cytokines on behavioral, affective, and cognitive changes including serotonin, noradrenaline, and tryptophan metabolism [13,14]. Although no association between CRP and changes in depression and FMD were observed in the present analysis, future comprehensive examination of the proinflammatory cytokine profile with dietary interventions is warranted. Moreover, several studies have shown that obesity increases plasma cortisol levels [15,16] and that cortisol also is elevated in depressed patients [17]. High levels of cortisol are related to inflammation [18], and have been shown to impair endothelial function [19]. It is therefore possible that the lack of association between CRP and changes in FMD might have been, at least in part, due to elevated cortisol also affecting FMD. Unfortunately, however, it is a limitation of the present study that cortisol levels were not measured. Previous studies also show that peripheral artery function and blood flow regulation are also closely

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associated with cerebrovascular response [20] and that vasodilator intervention increase brachial artery FMD and cerebrovascular responsiveness simultaneously [21]. Thereby, because impaired cerebral blood flow exists in depression [22], the possibility that the association between brachial artery FMD and depression is mediated by cerebral blood flow dysfunction cannot be dismissed and should be assessed in future studies. Prior research has reported reductions in depression [23], and improvements in FMD [24], with weight loss and associations between insulin resistance and FMD [24]. Insulin resistance also has been previously associated with depression [25], although this has only shown to be a weak association [26], and not present in all studies [27]. In the present analysis, the association between depression and FMD occurred independently of changes in weight or insulin resistance. This suggests inflammation may directly or indirectly mediate changes in depressive state, independent of adiposity and insulin resistance. The present analysis also showed the association between the changes in depression and FMD occurred independent of diet pattern assignment. Although there were macronutrient differences between the LC and HC diets that have been previously associated with mood or depression alternations including carbohydrate [28], or saturated fat [29], dietary intake of any macronutrient was not associated with the changes in depression (data not shown). It is possible that the association between depression and FMD may be masking any subtle effect of individual nutrients that occurred with the dietary modulations. Alternatively, the effects of diet composition on depression or FMD may not be isolated to a specific diet component and any individual association may be too weak to be detected. The error and variance associated with dietary data also may prevent associations between changes in depression and specific dietary components to be realized. A limitation of the present study is that the relatively small sample size also may have limited the associations between changes in depression and other variables from being realized. Conclusion A significant independent association between FMD and depression following either an energy-restricted LC or HC diet occurred independently of changes in body weight and insulin resistance. Although the present findings only represent an association between depression and FMD and do not permit any determination of causation or directionality, these data support a mechanistic association between depression and endothelial function, which may be mediated by inflammation and potentially influence long-term health. It is possible that intervention strategies that adversely affect mood or depression might negatively affect endothelial function and CVD risk in overweight and obese adults or vice versa. Acknowledgments This study was supported by project grants from the National Heart Foundation of Australia and the National Health and Medical Research Council of Australia. Simplot Australia, Mt Buffalo Hazelnuts Victoria, Webster Walnuts Victoria, Stahmann Farms Queensland, and Scalzo Food Industries Victoria donated foods for this study. None of the funding agencies played a role in the conception, design, or conduct of the study, collection, management, analysis, and interpretation of the data; or preparation, review, and approval of the manuscript. LJM is supported by a National Heart Foundation Fellowship.

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We thank the volunteers who made the study possible through their participation. We gratefully acknowledge the work of Clinical Research Team at the Commonwealth Scientific and Industrial Research Organisation – Animal, Food and Health Sciences, Adelaide, South Australia, Australia including Kathryn Bastiaans, Julia Weaver, Anne McGuffin, and Vanessa Courage for coordinating the trial; Xenia Cleanthous, Gemma Williams, and Julianne McKeough for assisting in implementing the dietary intervention and collection of dietary data; Rosemary McArthur and Lindy Lawson for nursing expertise; Thomas Wycherley for collecting the FMD data, Mark Mano, Candita Sullivan, Julie Turner, and Cathryn Pape for performing the biochemical assays; and Julie Syrette for assisting with data management.

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