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. Author manuscript; available in PMC: 2024 Jan 1.
Published in final edited form as: J Cardiovasc Nurs. 2022 Apr 8;38(1):6–12. doi: 10.1097/JCN.0000000000000912

Dietary Antioxidant Insufficiency Is Associated with Increased Inflammatory Markers and Poorer Health-related Quality of Life in Patients with Heart Failure

Jia-Rong Wu 1, Eun Kyeung Song 2, Debra K Moser 3, Terry A Lennie 4
PMCID: PMC9547034  NIHMSID: NIHMS1785308  PMID: 35404329

Abstract

BACKGROUND:

Antioxidant insufficiency, elevated inflammatory markers, and poor health-related quality-of-life (HRQOL) are prevalent in patients with heart failure (HF).

OBJECTIVE:

The objective of this study was to examine the associations among dietary antioxidant intake, inflammatory markers and HRQOL in patients with HF.

METHODS:

This was a secondary analysis of 265 HF patients who completed a 4-day food diary. We assessed intake of 10 antioxidants: alpha-carotene, beta-carotene, beta-cryptoxanthin, lutein, zeaxanthin, lycopene, vitamin C and E, zinc, and selenium. Antioxidant insufficiency was reflected by a measured level for each antioxidant that was below the estimate average requirement (EAR) or lower than median for antioxidants without an EAR. Inflammatory markers including serum C-reactive protein (CRP), cytokines (interleukin 6, 10), tumor necrosis factor-alpha (TNFα), and soluble receptors (sTNFR1 and sTNFR2) were assessed with enzyme immunoassay. HRQOL was measured using the Minnesota Living with Heart Failure at 12 months.

RESULTS:

Dietary antioxidant insufficiency predicted CRP (β=.135, P=.032) and IL-10 (β=−.155, P=.027). Patients with higher antioxidant insufficiency had higher CRP and lower IL10. Both antioxidant insufficiency (β=.13, P=.049) and higher CRP (β=.16, P=.019) were independently associated with poorer HRQOL while adjusting for covariates.

CONCLUSIONS:

Dietary antioxidant insufficiency was associated with increased markers of inflammation and poorer HRQOL. Improvement of diet quality among patients with HF may be a fruitful area of research for enhancing HRQOL.

Keywords: Dietary antioxidant insufficiency, heart failure, inflammatory marker, quality of life

INTRODUCTION

Antioxidants are substances that scavenge free radicals produced by both beneficial and pathologic metabolic processes.1 Vitamins C and E, and lycopene are among the most potent dietary antioxidants.2 Dietary antioxidant insufficiency can result in oxidative stress, which occurs when the production of free radicals exceeds the antioxidant capacity of the body. In healthy older adults, dietary antioxidant insufficiency results in increased inflammatory activity,2,3 higher risk of cardiovascular events (e.g., myocardial infarction, heart failure),4,5 and poor health-related quality-of-life (HRQOL).6 In contrast, adequate dietary antioxidant intake is associated with prolonged survival, decreased inflammation, and improved lung function.7

Patients with heart failure (HF) are more likely to have dietary antioxidant insufficiencies than healthy adults, as well as higher production of free radicals and inflammation.8–10 Many investigators have demonstrated that inflammatory markers such as C-reactive protein (CRP) are significantly elevated in patients with HF.11 These studies provide a foundation to explore the relationship between dietary antioxidant intake and levels of inflammatory markers in HF.

In addition to having more antioxidant insufficiencies, patients with HF have poorer HRQOL than healthy adults.12 Researchers have suggested there is a positive relationship between dietary antioxidant supplementation and better HRQOL in patients with chronic illness.6,13 For example, patients who received vitamin E supplementation experienced significantly improved HRQOL compared with those who did not receive vitamin E supplementation.13 Similarly, in other RCTs, dietary antioxidant supplementation increased the activity of antioxidant enzymes, and reduced markers of inflammation and oxidative stress, as well as improved HRQOL in patients with chronic illness.6 However, there are only a few studies in which investigators have examined the relationship between dietary antioxidants and HRQOL in patients with HF.14–16

Figure 1 illustrates the conceptual framework for this study. Heart failure is a consequence of cardiac remodeling, a pathophysiological process that involves structural and functional alterations, including ventricular dilatation, impairment of pump function, and changes in the sympathetic nervous and renin-angiotensin-aldosterone systems. Consequently, patients with HF commonly have low cardiac output, fluid overload, and hypoxia/hypoxemia, which triggers increased production of oxygen-free radicals and oxidative stress.17 Free radicals interact with nitric oxide resulting in lower endothelial nitric oxide levels. Nitric oxide is an essential molecule for vascular smooth muscle relaxation and vasodilation.1 Thus, decreased in nitric oxide can increase vascular resistance. Insufficient dietary intake of antioxidants further contributes to oxidative stress that results in oxidative cellular damage and production of proinflammatory cytokines,8 increased myocardial workload, decreased cardiac output, and worsened HRQOL.18

Figure 1:

Figure 1:

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Conceptual framework

Due to high prevalence of dietary antioxidant insufficiency in patients with HF,12 and potential negative impact of antioxidant insufficiency on inflammation and HRQOL, it is important to explore the relationships among those variables in patients with HF. Accordingly, the purpose of this study was to examine the associations among dietary antioxidant intake, inflammatory markers and HRQOL in patients with HF.

METHODS

Study Design

This was a secondary data analysis from a prospective cohort study.19 Participants’ sociodemographic, and clinical data were collected by patient interview and medical record review at baseline. A detailed 4-day food diary was used to determine dietary antioxidant consumption. Blood was drawn at baseline to measure levels of inflammatory markers. HRQOL data were collected by patient interview at 12 months by phone.

Samples and Setting

Detailed eligibility criteria and recruitment methods have been published previously.19 Those with a confirmed diagnosis of chronic HF were recruited and enrolled in this study from three large community hospitals or academic medical centers in three Midwestern/Southern states. We excluded those with a comorbid inflammatory condition, terminal illness, or obvious cognitive impairment that precluded provision of informed consent.

Measures

Dietary antioxidant insufficiency.

A 4-day (3 weekdays and 1 weekend day) food diary was used to collect data on dietary antioxidant intake. The 4-day food diary is reliable, valid, and commonly used by researchers to measure dietary intake.20 We chose a 4-day food diary to reduce participant burden and increase accuracy of the dietary data.20 In addition, we chose to collect data on 3 weekdays and 1 weekend day to better reflect participants’ usual dietary patterns.20 Nutrition Data Systems-R (NDS-R) software (NCC, University of Minnesota) was used to analyze data from the food diary. Averaged 4-day intake of ten dietary nutrients that are designated as antioxidants (alpha-carotene, beta-carotene, beta-cryptoxanthin, lutein, zeaxanthin, lycopene, vitamin C and E, zinc, selenium)21 were included in this study. Among these 10 antioxidants, 4 (vitamin C, E, zinc and selenium) have an estimated average requirement (EAR) established by the National Academy of Medicine (formally Institute of Medicine).22 Insufficiency of vitamin C, E, zinc and selenium was defined as intake below the EAR. Insufficiency of antioxidants without an established EAR (i.e., alpha-carotene, beta-carotene, beta-cryptoxanthin, lutein, zeaxanthin, lycopene) was defined as intake lower than the group median. The number of dietary antioxidant insufficiencies was summed with higher number indicating greater dietary antioxidant insufficiency.

Inflammatory biomarkers.

Serum for C-reactive protein (CRP), cytokines (interleukin (IL)-6, IL-10), tumor necrosis factor alpha (TNFα), and soluble receptors of TNF alpha (sTNFR1 and sTNFR2) was drawn by venipuncture the morning following completion of the food diaries and measured with enzyme-linked immunoassay. These inflammatory biomarkers were chosen because oxidative stress triggers release of cytokines.23,24 TNFα indicates presence of an inflammatory stimulus, and the receptors (sTNFR1 and sTNFR2) indicate that an inflammation response has been initiated.23,24 Blood was centrifuged within 30 minutes. Serum was placed in aliquots and stored at −70°C until analyzed in the same core laboratory. Any samples with intra-assay coefficients of variation >10% were rerun until subsequent coefficients of variation were acceptable.

Health-related quality of life (HRQOL).

HRQOL was measured using the 21-item, Minnesota Living with Heart Failure questionnaire (MLHFQ) that assesses patients’ perceptions of the influence of HF on physical and emotional aspects of life.25 The 21 items are summed and the totals can range from 0–105 with higher scores indicating worse HRQOL. This instrument is a disease-specific scale and has been widely used to measure health-related quality of life in this population.26 Researchers have demonstrated evidence for validity and reliability.25 In this study, the Cronbach’s alpha for the total score was 0.95.

Covariates

Age, sex, race, living status (living with others or alone), left ventricular ejection fraction (LVEF), body mass index (BMI), comorbidities, total energy intake, and medication use (angiotensin-converting-enzyme inhibitor [ACEI] and beta-blockers) were collected as covariates as they were associated with HRQOL, dietary antioxidants and/or inflammatory markers.4,8,27–29 Data were collected by patient interview and medical record review.30 Comorbidity was measured using the Charlson Comorbidity Index.30 Patients’ energy intake was defined as the averaged daily total kcals obtained from all proteins, fats, and carbohydrates consumed over the 4-days.

Procedure

We obtained permission to conduct the study from the Institutional Review Board (IRB) at all sites. A trained research nurse visited patients in their home to explain the study and obtain informed, written consent. Digital scales to measure food, and face-to-face and written instructions were given to patients on how to use digital scales, how to measure the weight of foods to be eaten and how to record foods eaten in the 4-day food diary. The research nurse contacted patients by phone on Day 1 to remind them to start recording the food diary and to verify accuracy of recording. The 4-day food diaries were reviewed by a registered dietitian to verify serving sizes, ingredients in homemade dishes, and preparation methods at baseline. We collected baseline data that included blood draw to assess levels of inflammatory markers at General Clinical Research Centers (GCRC). Patients were interviewed by phone to complete the MLHFQ to assess HRQOL at 12 months.

Data Management and Analysis

All data analyses were done using IBM SPSS version 27.0 (Armonk, NY). A significance level of .05 was used throughout. All continuous inflammatory marker data were reported as the median with the interquartile range. Logarithmic transformations were used to transform CRP, IL-6, IL-10, TNFα, and sTNFR1 and sTNFR2 to result in normal distributions for these data and transformed data were used in independent t-tests and multiple linear regression analysis. HRQOL data were normally distributed as the skewness and kurtosis of the HRQOL were within ±1 (skewness=.281 and kurtosis=−.783), and the plots in the QQ plot followed the trend line. We used linear regression to examine whether dietary antioxidant insufficiency predicted inflammatory markers and whether dietary antioxidant insufficiency and inflammatory markers predicted HRQOL with and without adjusting for demographic and clinical variables.

RESULTS

Patient characteristics

Two hundred and sixty-five patients with HF were included in this study (Table 1). Two thirds (67%) of patients were male. A quarter of patients (26%) were African Americans. About one third of patients (31%) had HF symptoms with less than ordinary activities (NYHA class III) and 13% had HF symptoms at rest (NYHA class IV). About half of patients were single, divorced, or widowed (42%, n=111). The majority were taking ACEIs (70%, n=179) and beta blockers (89%, n=234) and had government medical insurance (76%, n=201).

Table 1:

Demographic and clinical characteristics of participants

Characteristics Overall
(N = 265)
Age, years 61 ±12
Female (%) 87 (33)
African American (%) 69 (26)
Marital status, married/cohabitated (%) 154 (58)
Education, years 14 ±3
Left ventricular ejection fraction, % 33.5 ±13.2
New York Heart Association class, III/IV (%) 117 (44)
Etiology, Ischemic 123 (47)
 Hypertensive 40 (15)
 Others 97 (37)
Body mass index, kg/m2 30.4 ±7.0
Comorbidities 3 ±1.8
Taking angiotensin-converting enzyme inhibitor (%) 179 (70)
Taking beta-blocker (%) 234 (89)
Medical insurance--Government 201 (76)
Medical insurance-Commercial 96 (36)
No medical insurance 15 (6)
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Dietary Antioxidant Insufficiency and Inflammatory Markers

A total of 41% of patients did not meet the EAR for vitamin C, 60% for vitamin E, 46% for dietary zinc, and 50% were below the median for alpha-carotene, beta-carotene, beta-cryptoxanthin, lutein, zeaxanthin, and lycopene. Most patients (96%) met the EAR for selenium. The median number of dietary antioxidant insufficiencies was 4. Only 21 patients (8%) had no dietary antioxidant insufficiency.

Dietary antioxidant insufficiency was positively correlated with CRP (r =.135, P=.032) and negatively correlated with IL-10 (r = −.155, P=.027). There were no significant correlations among dietary antioxidant insufficiency and other inflammatory markers (TNFα, IL6, IL10, sTNFR1, sTNFR2, all P>.05). In multiple linear regression, patients with higher dietary antioxidant insufficiency had higher levels of CRP (β=.133, P=.044) and lower levels of IL10 (β= −.155, P=.024) after adjusting for gender, ACEI use, NYHA, comorbidity, and total energy intake.

Dietary Antioxidant Insufficiency, Inflammatory Markers, and Health-related Quality of Life

The mean score for the MLHFQ was 42.1 (± 25.5). In unadjusted linear regression, higher dietary antioxidant insufficiency (β=.212, P=.002) and higher CRP (β=.285, P<.001) were associated with poorer HRQOL. The multiple regression model for prediction of MLHFQ score is shown in Table 2. Both higher dietary antioxidant insufficiency (P=.048) and higher CRP (P=.018) independently predicted poorer HRQOL, while adjusting for demographic and clinical variables (i.e., age, gender, race, living status, LVEF, ACEI use, beta-blocker use, BMI, comorbidity, and total energy intake). In each adjusted regression model, all variance inflation factors were < 1.2, suggesting no parameter distortion due to multicollinearity.

Table 2.

Prediction of Health-related Quality of Life in Patients with Heart Failure (N = 265)

Variable Beta Significance
Without covariate adjustment
Dietary antioxidant insufficiency .212 .002
F=9.884, P=.002
Without covariate adjustment
C-reactive Protein .285 <.001
F=18.533, P<.001
Without covariate adjustment
Dietary antioxidant insufficiency .154 .023
C-reactive Protein .252 <.001
F=11.764, P<.001
With covariate adjustment
Age −.120 .089
Sex −.058 .428
Race .153 .025
Living with others .064 .337
Left ventricular ejection fraction .052 .470
Body mass index .108 .146
Comorbidity .241 <.001
Beta-blocker use −.074 .266
Angiotensin-converting-enzyme inhibitor use −.095 .159
Total energy intake −.052 .466
Dietary antioxidant insufficiency .149 .035
C-reactive Protein .182 .013
F=4.83, P<.001
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DISCUSSION

Heart failure is a chronic inflammatory condition that causes significant morbidity and poor HRQOL.31 In this study, we examined the relationships among dietary antioxidant insufficiency, inflammatory markers and HRQOL in patients with HF. As hypothesized in our framework, we demonstrated that dietary antioxidant insufficiencies were associated with CRP, which is consistent with prior studies.3,32,33 For example, Oliverira, et al. found that those with higher intake of antioxidants had lower levels of high sensitivity CRP.32 Consistently, patients with dietary antioxidant insufficiencies had significantly lower levels of IL-10 in our study. IL-10 is an anti-inflammatory cytokine released by immune cells that inhibits production of proinflammatory cytokines.34,35 Palacz-Wrobel et al. found that an antioxidant-rich diet (kaempferol and resveratrol) was associated with increased IL-10 levels. 35 Oxidative stress is closely interrelated with inflammation.36 When patients have insufficient intake of antioxidants, they have higher risks of increased oxidative stress that results in lower levels of anti-inflammatory cytokines.8,37 Therefore, increasing intake of antioxidant-rich foods to prevent antioxidant insufficiency may reduce inflammation in patients with HF, although this hypothesis remains untested.

We also found that dietary antioxidant insufficiency was associated with poorer HRQOL. There are only limited studies on the relationship between circulating antioxidants and HRQOL in the literature, especially in HF.29,38 The DASH or the Mediterranean diet is characterized by high consumption of fruits, vegetables, legumes, and whole grains, which offer rich sources of antioxidant compounds.39 Following the DASH or the Mediterranean diet has been associated with higher dietary antioxidant intake and better HRQOL.39 In a large multi-center, observational study of 2,382 patients with HF, those with an insufficiency in the antioxidant selenium were more likely to have HF symptoms and poorer HRQOL.38 In a small randomized controlled trial of 30 patients with HF,29 serum antioxidant concentrations among patients in the intervention group who were given a supplement of 15 vitamins/minerals that included vitamin C, E, zinc and selenium had a significant improvement in HRQOL compared to the placebo group. Therefore, increasing dietary antioxidant intake (from food and/or supplements) to prevent dietary antioxidant insufficiency may improve HRQOL in patients with HF.

Other investigators have also found that higher CRP levels were associated with poorer HRQOL.40,41 It is unclear why other inflammatory markers (IL-6, IL-10, TNFα, sTNFR1, and sTNFR2) were not associated with HRQOL. However, mixed results regarding the relationship between IL-6, IL-10, and TNFα with HRQOL have been previous reported. For example, in a cross-sectional study, researchers found increased levels of IL-6 and lower levels of IL-10 were related to worse HRQOL, but not TNFα.24 In a prospective study,23 investigators reported that an increased level of TNFα at 12 months was associated with a decrease in HRQOL from baseline to 12 months. Higher levels of baseline sTNFR2 and both sTNFR1 and sTNFR2 levels at 12months were associated with worse baseline HRQOL. No significant relationships with the HRQOL were observed for IL-6 or IL-10 at baseline or 12 months.23 It is possible that different inflammatory cytokines have different physiological functions that may impact HRQOL in different ways at different time points.23,24,42 The findings from prior studies and our study highlight the complex relationship between inflammatory cytokine(s) and HRQOL.42

Of concern is that only 8% of the participants in our study had no dietary insufficiency of 10 antioxidants we assessed. Compared with healthy adults, patients with HF are more likely to have dietary antioxidant insufficiencies.8,9 Lewis and colleague reported 40% of healthy Americans reached the recommended levels of consumption for multiple antioxidants that were measured by 24-hour dietary recalls, including vitamin E, carotene, zinc, and selenium.43 These findings demonstrated high prevalence of dietary antioxidant insufficiencies in adults, especially in patients with HF. However, there were no published studies on why patients with HF are likely to have dietary antioxidant insufficiency, an important topic for future research.

Limitations

Our study has several limitations. First, dietary antioxidant intake, inflammatory markers, and HRQOL, were collected at one time point, which might not reflect dietary pattern of antioxidant intake, nor inflammatory markers/HRQOL changes over time. A longitudinal study with repeated measurements of dietary antioxidant intake, inflammatory markers, and HRQOL is needed to confirm our findings. Second, dietary antioxidant intake was assessed using the 4-day food diary, which has been used widely to assess nutritional intake;20 however, self-reported food diaries are subject to potential recording errors and social desirability20 and we did not confirm antioxidant intake using serum antioxidant concentrations. However, food diary is a valid method to measure dietary antioxidant intake as researchers have shown significant correlations between dietary intake measured by assessment of food diary and serum antioxidant concentration.44 Third, as this is a secondary data analysis, we were unable to adjust some important covariates (e.g., biomarkers of oxidative stress) that were not collected in the parent study.1 Therefore, our findings warrant further study to confirm our results.

CONCLUSIONS

We found that dietary antioxidant insufficiency was associated with higher levels of proinflammatory CRP, lower levels of anti-inflammatory IL-10, and poorer HRQOL. These results combined with previous research suggest that improvement of diet quality among patients with HF may be a fruitful area of research for enhancing HRQOL.

Acknowledgements/Sources of funding:

This study was supported by funding from the National Institute of Nursing Research of the National Institutes of Health under Award Number NR009280 (Lennie, T., PI) and the National Research Foundation of Korea (NRF) Grant by the Korean Government (NRF-2018R1D1A1A09083498) (Song, E. K., PI). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Nursing Research or the National Institutes of Health.

Footnotes

Conflict of Interest: The authors have no conflicts of interest to declare.

Contributor Information

Jia-Rong Wu, University of Kentucky, College of Nursing.

Eun Kyeung Song, Department of Nursing, College of Medicine, University of Ulsan, Korea.

Debra K. Moser, University of Kentucky, College of Nursing.

Terry A. Lennie, University of Kentucky, College of Nursing.

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