Associations of Serum Carotenoids With Risk of All‐Cause and Cardiovascular Mortality in Hypertensive Adults

Xu Zhu; Iokfai Cheang; Yuan Tang; Mengsha Shi; Qingqing Zhu; Rongrong Gao; Shengen Liao; Wenming Yao; Yanli Zhou; Haifeng Zhang; Xinli Li

doi:10.1161/JAHA.122.027568

. 2023 Feb 8;12(4):e027568. doi: 10.1161/JAHA.122.027568

Associations of Serum Carotenoids With Risk of All‐Cause and Cardiovascular Mortality in Hypertensive Adults

Xu Zhu ^1,^*, Iokfai Cheang ^1,^*, Yuan Tang ¹, Mengsha Shi ¹, Qingqing Zhu ¹, Rongrong Gao ¹, Shengen Liao ¹, Wenming Yao ¹, Yanli Zhou ¹, Haifeng Zhang ^2,^✉, Xinli Li ^1,^✉

PMCID: PMC10111495 PMID: 36752230

Abstract

Background

Systemic oxidative stress is involved in the development of hypertension, whereas carotenoids are a group of natural antioxidants. Our study aims to evaluate the relationships between the serum concentrations of major carotenoids and mortality in hypertensive adults.

Methods and Results

Data on 5 serum carotenoids from the National Health and Nutrition Examination Survey (NHANES) III and NHANES 2001–2006 were included. Outcome measures (all‐cause and cardiovascular mortality) were identified from the National Death Index through December 31, 2019. Multiple Cox proportional hazards regression and restricted cubic spline analyses were performed to determine the association between carotenoid levels and outcomes. A total of 8390 hypertensive adults were included in the analysis. At a median follow‐up duration of 16.6 years, all‐cause and cardiovascular mortality occurred in 4005 (47.74%) and 1205 (14.36%) participants, respectively. Compared with the lowest quartiles, the highest quartiles of 5 major serum carotenoids were associated with lower risk of all‐cause mortality, with multivariable‐adjusted hazard ratios (HRs) of 0.63 (95% CI, 0.56–0.71) for α‐carotene, 0.70 (95% CI, 0.61–0.80); for β‐carotene, 0.67 (95% CI, 0.58–0.76); for β‐cryptoxanthin, 0.74 (95% CI, 0.64–0.86) for lycopene; and 0.72 (95% CI, 0.63–0.83) for lutein/zeaxanthin. For cause‐specific mortality, this association with the fourth quartile of serum carotenoids was evident for a reduced rate of cardiovascular mortality, with a 32% reduction for α‐carotene (HR, 0.68 [95% CI, 0.55–0.86]), a 29% reduction for β‐cryptoxanthin (HR, 0.71 [95% CI, 0.56–0.89]), and a 26% reduction for lycopene (HR, 0.74 [95% CI, 0.59–0.94]), but not for β‐carotene and lutein/zeaxanthin. In addition, we found that serum α‐carotene, β‐carotene, β‐cryptoxanthin, and lutein/zeaxanthin levels were nonlinearly related to all‐cause mortality with inflection points of 2.43, 8.49, 5.12, and 14.17 μg/dL, respectively. Serum α‐carotene, β‐cryptoxanthin, and lutein/zeaxanthin concentrations showed nonlinear associations with cardiovascular mortality with inflection points of 2.31, 5.26, and 15.40 μg/dL, respectively.

Conclusions

Findings suggest that higher serum carotenoid concentrations were associated with lower risks of all‐cause and cardiovascular mortality in hypertensive adults.

Keywords: all‐cause mortality, cardiovascular mortality, carotenoids, hypertension, NHANES

Subject Categories: Diet and Nutrition, Epidemiology, Hypertension, Mortality/Survival, Disparities

Nonstandard Abbreviations and Acronyms

NHANES: National Health and Nutrition Examination Survey

Clinical Perspective.

What Is New?

This is a prospective study investigating the relationship between 5 serum carotenoid concentrations and all‐cause and cardiovascular mortality in 8390 hypertensive adults over a median follow‐up time of 16.6 years.
Lower serum carotenoids (α‐carotene, β‐carotene, β‐cryptoxanthin, lycopene, and lutein/zeaxanthin) concentrations were associated with a higher risk of all‐cause and cardiovascular mortality in hypertensive adults.

What Are the Clinical Implications?

The selected 5 major serum carotenoids levels might be nutrient biomarkers for the risk assessment of long‐term mortality in hypertensive adults, and the decreased carotenoid levels call for the optimization of the dietary structure and actions against nutritional insufficiency.

Hypertension is a major global public health challenge. ¹ The prevalence of hypertension has continued to increase over the years. In 2010, an estimated 1.39 billion persons worldwide were diagnosed with hypertension; by 2025, this number is projected to increase to 1.56 billion. ¹ , ² Hypertension, which is the leading risk factor for cardiovascular mortality, ³ emerges as vascular dysfunction because of a prolonged condition of heightened autoimmunity, inflammation, and oxidative stress. ⁴ Increasing evidence suggests that antioxidant micronutrients have a key role in the prevention of cardiovascular mortality. ⁵ , ⁶ , ⁷

Studies have had inconsistent results regarding the effects of carotenoids on human health. There are observational studies or interventions with carotenoid supplementation, particularly β‐carotene, where carotenoids have generated either null effects or harmful effects on all‐cause and/or cardiovascular mortality in different populations. ⁸ , ⁹ In contrast, carotenoids significantly reduce blood pressure (BP) in hypertensive patients ¹⁰ and reduce atherosclerosis progression in adults. ¹¹ Observational epidemiological studies have shown that higher dietary carotenoid intake levels or serum carotenoid concentrations are linked with a lower incidence of cardiovascular disease (CVD) ¹² , ¹³ and hypertension, ¹⁴ and a lower risk of mortality. ¹⁵ , ¹⁶ , ¹⁷ , ¹⁸ , ¹⁹ , ²⁰ , ²¹ , ²² , ²³ , ²⁴ , ²⁵ Furthermore, a meta‐analysis of longitudinal studies that examined the relationships between plasma or serum concentrations of several different types of carotenoids and mortality found that total carotene, α‐carotene, β‐carotene, and lycopene concentrations were inversely linked with the risk of all‐cause mortality. ²⁶ Carotenoids are thought to have protective effects against CVD and may reduce cardiovascular mortality because of their antioxidant stress effect. ²⁷ , ²⁸ In the meantime, oxidative stress has been identified as the unifying factor linking complex regulatory systems that sustain the pathophysiology of hypertension. ²⁹ However, evidence on the cardiovascular effects of carotenoids is scarce. There has not been a study that has followed hypertensive populations over a long period to determine whether or not blood carotenoids are connected with the risk of death from all causes or CVD.

Herein, we hypothesized a relationship between serum antioxidant micronutrients, carotenoids, and the mortality risk in a hypertensive population. The National Health and Nutrition Examination Survey (NHANES) is a long‐term epidemiological survey with a representative sampling design conducted in the United States. Because of the excellent quality of the survey and the availability of mortality data, this study aimed to determine the relationship between serum carotenoid (α‐carotene, β‐carotene, β‐cryptoxanthin, lycopene, and lutein/zeaxanthin) concentrations and all‐cause and cardiovascular mortality in hypertensive adults using data from NHANES III and NHANES 2001–2006.

Methods

All data are publicly available and can be accessed at the NHANES website (https://wwwn.cdc.gov/nchs/nhanes/continuousnhanes/default.aspx). Relevant R code is available upon request to the corresponding author.

Study Population

The NHANES is a long‐term epidemiology survey that uses a multistage, cluster‐sampling strategy to ensure that samples obtained from the United States are representative on a national scale (https://wwwn.cdc.gov/nchs/nhanes/default.aspx). The National Center for Health Statistics conducted the NHANES III, a survey of Americans' health and nutritional status, between 1988 and 1994. The survey evolved into a continuous program in 1999, publishing new data every 2 years. Each year, the survey investigates a sample of 5000 participants who are roughly nationally representative. The National Center for Health Statistics Research Ethics Review Board approved the research protocols, and all participants provided written informed consent.

Since the cycles containing serum carotenoid data were NHANES III, NHANES 2001–2002, 2003–2004, and 2005–2006, the representative data from NHANES III (1988–1994) and NHANES 2001–2006 were analyzed in this study. We enrolled eligible participants with hypertension aged >18 years who had complete data on 5 serum carotenoids. We excluded the following categories of participants: (1) participants who were pregnant, (2) participants with malignancies and CVDs, (3) participants with extreme energy intake (men: >8000 or <500 kcal/d; women: >5000 or <500 kcal/d), ³⁰ and (4) participants without follow‐up information.

Definition of Hypertension

After 5 minutes of resting, a qualified medical examiner repeated BP measurements at 30‐second intervals 3 (sometimes 4) times according to a standardized protocol. Individuals were hypertensive if they met 1 or more of the following criteria: (1) mean systolic BP ≥140 mm Hg, (2) mean diastolic BP ≥90 mm Hg, (3) ongoing antihypertensive treatment, and (4) self‐reported physician diagnosis of hypertension. ¹

Measurement of Serum Carotenoid Levels

Using high‐performance liquid chromatography, serum concentrations of α‐carotene, β‐carotene, β‐cryptoxanthin, lycopene, and lutein/zeaxanthin were measured in NHANES III, NHANES 2001–2002, and 2005–2006. However, the 5 serum carotenoids were quantified using a similar and comparable high‐performance liquid chromatography technique with a multiwavelength photodiode array absorbance detection at 450 nm in NHANES 2003–2004. Using regression analysis, NHANES 2003–2004 data were converted to equivalent carotenoid measurements based on high‐performance liquid chromatography. NHANES III and NHANES 2001–2006 both detected 5 carotenoids; however, NHANES 2001–2002 did not identify total lycopene. The total concentrations of serum carotenoids were derived by adding the concentrations of the 5 serum carotenoids. Detailed measurements are available at: https://wwwn.cdc.gov/nchs/nhanes/continuousnhanes/labmethods.aspx?Cycle=2003–2004.

Outcome Variables

The National Center for Health Statistics has linked data to the death certificate records of the National Death Index and has generated the public‐use linked mortality file for the NHANES III and NHANES 2001–2006. The follow‐up period was computed from the NHANES interview date to the registered date of death or censoring date (December 31, 2019). All individuals aged ≥18 years with sufficient identifying data were eligible to complete the mortality follow‐up. The National Center for Health Statistics determined underlying causes of death for participants based on the International Classification of Diseases, Tenth Revision (ICD‐10). The outcomes of the current study were all‐cause and cardiovascular (ICD codes I00–I99) mortality.

Covariate Analysis

In the NHANES, data collection was carried out using a standardized participant questionnaire during a household interview, two 24‐hour recall interviews (for assessing energy intakes), and a medical evaluation of each participant's age, sex, race, education level, poverty, smoking, physical activity, energy intake level, supplement use, antihypertensive medication use, and diabetes. Poverty was assessed using the poverty income ratio (the ratio of family income divided by a poverty threshold specific for family size using guidelines from the US Department of Health and Human Services) and defined as a poverty income ratio of <1 for a given family. ³¹ Participants who reported smoking <100 cigarettes in their lifetime were considered as never smokers. Participants who had smoked >100 cigarettes throughout their lifetime but had quit smoking were classified as former smokers, whereas those who were still smoking were classed as current smokers. Drinking status was categorized as nondrinker, low‐to‐moderate drinker (<2 drinks/d in men and <1 drink/d in women), or heavy drinker (≥2 drinks/d in men and ≥1 drinks/d in women). The intake of energy, nutrients, and other food components was calculated by averaging the 2 values from the two 24‐hour recall interviews. According to the Compendium of Physical Activities, ³² Physical activity was evaluated based on metabolic equivalent levels, and participants were categorized as inactive (no leisure‐time physical activity), insufficiently active (moderate activity 1–5 times per week with metabolic equivalent 3–6 or vigorous activity 1–3 times per week with metabolic equivalent >6), or active (those who had more moderate or vigorous activity than those described above). ³³ Measurements of total cholesterol (TC) and high‐density lipoprotein cholesterol in blood samples were obtained via laboratory tests. The estimated glomerular filtration rate (eGFR) was computed using the Chronic Kidney Disease‐Epidemiology Collaboration equation. ³⁴ Descriptions of each variable are presented in https://wwwn.cdc.gov/Nchs/Nhanes/continuousnhanes/.

Statistical Analysis

In accordance with the recommendations made by the National Center for Health Statistics, the primary sampling units, sample weights, and strata were all considered throughout the data analysis to provide reliable national estimates. The weighted analyses were conducted with the R package “survey.” Continuous variables were calculated as means (SEs) or medians (interquartile ranges) and compared using Student t test (normal distribution) or the Mann–Whitney U test (nonnormal distribution). Categorical variables were expressed as absolute values (percentages) and compared using the χ² test. All statistical analyses were performed with R Statistical Software, version 4.2.0, and P values of <0.05 (2‐sided) were deemed statistically significant.

For most covariates, <5.0% of the data were missing. However, there was a lack of data in 5.4% of the study participants for total energy intake levels, 7.8% for poverty income ratio, and 8.2% for drinking status. The missing data were multiply interpolated for the covariates by the “mice” package based on the random forest algorithm. The primary model included imputed values as the consistency with the model excluding participants with missing values was verified. The correlations for the 5 serum carotenoids were assessed using Spearman's correlation coefficient. The concentrations of each of the 5 carotenoids were log2‐transformed and divided into quartiles.

For all analyzed variables, the proportionality of risk required by the Cox model was assessed using Schoenfeld residuals, and none of the assumptions were violated. The linearity of risk was evaluated by restricted cubic splines for all of the continuous variables. Quantitative variables were fitted as a single continuous measurement (eg, age and eGFR), unless there was clear evidence of nonlinearity, as occurred with the total energy intakes, TC, high‐density lipoprotein cholesterol, systolic BP, and diastolic BP, which were converted to categorical variables based on clinical expertise or appropriately transformed to satisfy the linear relationship required for the consumption of the Cox model. In addition, we calculated variance inflation factors to examine the multicollinearity among the independent variables in the multiple Cox model. Three sequential multiple Cox proportional hazards regression models were used to investigate the relationships between each of the 5 serum carotenoids and the risk of all‐cause and cardiovascular mortality. Model 1 was adjusted for age (continuous), sex (male or female), and race and ethnicity non‐Hispanic White (yes or no). Model 2 was adjusted the same as for Model 1 plus the education level (below high school, high school, or above high school), family poverty income ratio (<1.0, or ≥1.0), smoking status (never smoker, former smoker, or current smoker), drinking status (nondrinker, low‐to‐moderate drinker, or heavy drinker), body mass index (<25.0, 25.0–29.9, or >29.9), total energy intakes (in quartiles), physical activity (inactive, insufficiently active, or active), TC (in quartiles), high‐density lipoprotein cholesterol (in quartiles), eGFR (continuous), supplement use (yes or no), and self‐reported diabetes (yes or no). Model 3 was based on Model 2 with additional adjustments for antihypertensive medication use (yes or no), systolic BP (<120, 120–129, 130–139, or ≥140 mm Hg), and diastolic BP (<70, 70–79, 80–89, or ≥90 mm Hg). In addition, restricted cubic splines was utilized to investigate dose–response relationships, using 3 knots (10th, 50th, and 90th percentiles). Nonlinearity was tested using ANOVA. The threshold inflection of linearity was calculated using a segmented regression to fit the piecewise‐linear association of individual carotenoids with the risk of all‐cause and cardiovascular mortality.

Multiple sensitivity analyses were performed to evaluate the robustness of the results. First, to minimize the possibility of reverse‐causality bias, individuals who died within the first 2 years of the study's follow‐up period were excluded from the study. Second, we further adjusted for individual dietary factors, such as intakes of total protein, total fat, cholesterol, fiber, and vitamins A, E, and C (all log2‐transformed), and nutrient biomarkers, including serum iron, folate, and vitamin B12, A, E, and C levels (all log2‐transformed). Finally, as a supplemental analysis, we assessed the association of dietary carotenoid intake levels with the risk of all‐cause and cardiovascular mortality among 12 206 hypertensive adults and data from NHANES 2001–2014.

Results

Characteristics of the Study Participants

There was a total of 13 688 hypertensive participants from NHANES III and NHANES 2001–2006. Among them, those with missing data on the 5 serum carotenoids (n=2173), pregnant women (n=95), cancer (n=1423), CVDs (n=1485), extreme energy intake (n=102), and without follow‐up information (n=20) were excluded. In total, 8390 eligible participants from NHANES III (n=4701) and NHANES 2001–2006 (n=3689) were enrolled (Figure S1).

Table 1 presents the sociodemographic and health status characteristics of enrolled participants. The study (hypertensive) population, with a mean age of 52.58 (0.36) years, was primarily female (52.21%). The mean systolic BP was 137.77 (0.41) mm Hg and the mean diastolic BP was 79.53 (0.29) mm Hg. At the census date (December 31, 2019), 4005 (47.74%) hypertensive adults died of all‐cause deaths and 1205 (14.36%) of cardiovascular deaths.

Table 1.

Baseline Characteristics of Adults With Hypertension in NHANES III and NHANES 2001–2006 (n=8390)

Variables	Total (n=8390)	All‐cause mortality		P value
Variables	Total (n=8390)	No (n=4385)	Yes (n=4005)	P value
Age, y	52.58±0.36	46.04±0.30	63.86±0.41	<0.001
Male, n (%)	4010 (47.79)	2098 (51.85)	1912 (45.96)	<0.001
Non‐Hispanic White, n (%)	3802 (45.32)	1743 (72.05)	2059 (79.01)	<0.001
Education level, n (%)				<0.001
Below high school	4762 (56.76)	1983 (31.43)	2779 (58.63)
High school	1490 (17.76)	917 (24.22)	573 (18.61)
Above high school	2138 (25.48)	1485 (44.35)	653 (22.76)
Poverty, n (%)	1756 (20.93)	835 (11.78)	921 (14.69)	0.002
Smoking status, n (%)				<0.001
Never smoker	4180 (49.82)	2398 (52.17)	1782 (40.74)
Former smoker	2074 (24.72)	930 (22.43)	1144 (30.24)
Current smoker	2136 (25.46)	1057 (25.40)	1079 (29.02)
Drinking status, n (%)				<0.001
Nondrinker	3147 (37.51)	1290 (24.39)	1857 (41.97)
Low‐to‐moderate drinker	4422 (52.71)	2643 (64.56)	1779 (46.87)
Heavy drinker	821 (9.79)	452 (11.05)	369 (11.17)
Body mass index, n (%)				<0.001
<25.0 kg/m²	1829 (21.8)	838 (20.11)	991 (24.34)
25.0–29.9 kg/m²	3405 (40.58)	1600 (36.87)	1805 (43.40)
>29.9 kg/m²	3156 (37.62)	1947 (43.02)	1209 (32.26)
Physical activity, n (%)				<0.001
Inactive	2233 (26.62)	975 (17.30)	1258 (26.84)
Insufficiently active	3789 (45.16)	2199 (55.41)	1590 (42.90)
Active	2368 (28.22)	1211 (27.29)	1157 (30.26)
Total cholesterol, mg/dL	209.00 [183.00, 239.00]	206.00 [180.00, 236.00]	214.00 [188.00, 244.00]	<0.001
HDL‐C, mg/dL	47.95 [39.83, 59.16]	47.95 [39.83, 59.16]	49.11 [39.83, 59.94]	0.350
eGFR, mL/min per 1.73 m²	81.25±0.50	88.68±0.50	68.43±0.56	<0.001
Energy intake, kcal/d	1999.00 [1513.00, 2605.01]	2180.00 [1660.05, 2739.00]	1721.00 [1331.54, 2269.00]	<0.001
Systolic blood pressure, n (%)				<0.001
<120 mm Hg	1169 (13.93)	885 (21.62)	284 (9.40)
120–129 mm Hg	1247 (14.86)	855 (20.73)	392 (10.72)
130–139 mm Hg	1583 (18.87)	934 (22.10)	649 (18.41)
≥140 mm Hg	4391 (52.34)	1711 (35.54)	2680 (61.47)
Diastolic blood pressure, n (%)				<0.001
<70 mm Hg	1794 (21.38)	832 (17.50)	962 (22.38)
70–79 mm Hg	2471 (29.45)	1321 (30.25)	1150 (29.18)
80–89 mm Hg	2301 (27.43)	1179 (28.21)	1122 (29.02)
≥90 mm Hg	1824 (21.74)	1053 (24.04)	771 (19.42)
Self‐reported diabetes, n (%)	1122 (13.37)	414 (7.05)	708 (14.68)	<0.001
Supplement use, n (%)	3742 (44.6)	1909 (49.75)	1833 (50.77)	0.480
Antihypertensive medication use, n (%)	6426 (76.59)	3183 (72.41)	3243 (80.44)	<0.001

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Normally distributed continuous variables are described as mean±SE, and continuous variables without a normal distribution are presented as median [interquartile range]. Categorical variables are presented as numbers (percentages). N reflects the study sample while percentages reflect the survey‐weighted. eGFR indicates estimated glomerular filtration rate; HDL‐C, high‐density lipoprotein cholesterol; and NHANES, National Health and Nutrition Examination Survey.

Participants in the all‐cause mortality group were older, more likely to be non‐Hispanic White, and had higher systolic BP, lower diastolic BP, a lower body mass index, lower energy intake levels, less physical activity, and more frequent abnormal laboratory parameters (eGFR, and TC). On the other hand, the participants in the all‐cause mortality group were more often poverty‐stricken and former and current smokers, had lower levels of education, a higher prevalence of diabetes, and used antihypertensive medications. There were no significant differences in dietary supplementation between the 2 groups.

Detection Distributions and Correlations Between Serum Carotenoids

The baseline distributions and concentrations of the 5 major serum carotenoids are shown in Table S1, with the highest mean concentration determined for lycopene (31.73 μg/dL), followed by lutein/zeaxanthin (19.72 μg/dL), β‐carotene (19.25 μg/dL), β‐cryptoxanthin (9.01 μg/dL), and α‐carotene (4.30 μg/dL). Detailed distribution data on individual serum carotenoids, dietary carotenoids, dietary factors, and serum nutrient biomarkers are presented in Table S1. The pairwise Spearman's correlation coefficients ranged from 0.05 to 0.71, suggesting overall weak to strong correlations between serum carotenoids. The strongest correlation was observed between α‐carotene and β‐carotene (r=0.71). In addition, similar correlations were also discovered between dietary carotenoids. The correlation coefficients between the same serum carotenoids and dietary carotenoids ranged from 0.23 to 0.31 (Figure S2).

Associations Between the 5 Serum Carotenoids and All‐Cause Mortality

During a median follow‐up period of 16.6 years, 4005 hypertensive adults with all‐cause deaths among 8390 individuals were identified. Table 2 presents the results of 3 multiple Cox regression analyses assessing the association of 5 serum carotenoids with the risk of all‐cause mortality in hypertensive adults. After adjustments for age, sex, and race and ethnicity, the 5 serum carotenoids were found to have significant associations with all‐cause mortality in Model 1. With further adjustments for the education level, family poverty income ratio, smoking and drinking status, body mass index, total energy intakes, physical activity, TC, high‐density lipoprotein cholesterol, eGFR, supplement use, and diabetes in Model 2, the results remained stable and statistically significant. In Model 3, compared with the respective lowest quartiles, the highest quartiles of 5 major serum carotenoids were associated with lower risk of all‐cause mortality after additional adjustments for antihypertensive medication use, systolic BP, and diastolic BP, with multivariable‐adjusted hazard ratios (HRs) of 0.63 (95% CI, 0.56–0.71, P _trend<0.001) for α‐carotene; 0.70 (95% CI, 0.61–0.80, P _trend<0.001) for β‐carotene; 0.67 (95% CI, 0.58–0.76, P _trend<0.001) for β‐cryptoxanthin; 0.74 (95% CI, 0.64–0.86, P _trend<0.001) for lycopene; and 0.72 (95% CI, 0.63–0.83, P _trend<0.001) for lutein/zeaxanthin. Similarly, in hypertensive adults, there was a significant link between total serum carotenoids and all‐cause mortality (Table S2).

Table 2.

Hazard Ratios (95% CIs) of All‐Cause Mortality According to Quartiles of Serum Carotenoids Concentrations Among Hypertensive Adults in NHANES III and NHANES 2001–2006

	Serum carotenoids (μg/dL)
	Quartile 1	Quartile 2	Quartile 3	Quartile 4	P _trend
α‐Carotene
Range	<1.51	1.51–3.00	3.01–5.19	>5.19
No. deaths/total	823/2177	847/2195	877/2009	865/2009
Model 1	1 [Reference]	0.73 (0.65–0.82)	0.60 (0.53–0.68)	0.49 (0.43–0.55)	<0.001
Model 2	1 [Reference]	0.77 (0.69–0.85)	0.68 (0.59–0.77)	0.62 (0.55–0.70)	<0.001
Model 3	1 [Reference]	0.77 (0.69–0.86)	0.68 (0.60–0.78)	0.63 (0.56–0.71)	<0.001
β‐Carotene
Range	<8.01	8.01–14.19	14.20–24.99	>24.99
No. deaths/total	744/2196	753/2057	873/2065	1042/2072
Model 1	1 [Reference]	0.72 (0.62–0.84)	0.62 (0.54–0.70)	0.56 (0.49–0.64)	<0.001
Model 2	1 [Reference]	0.77 (0.66–0.91)	0.74 (0.65–0.84)	0.69 (0.60–0.80)	<0.001
Model 3	1 [Reference]	0.78 (0.66–0.91)	0.74 (0.65–0.84)	0.70 (0.61–0.80)	<0.001
β‐Cryptoxanthin
Range	<5.00	5.00–7.99	8.00–12.69	>12.69
No. deaths/total	818/1922	903/2220	869/2127	822/2121
Model 1	1 [Reference]	0.83 (0.74–0.93)	0.63 (0.55–0.71)	0.53 (0.46–0.61)	<0.001
Model 2	1 [Reference]	0.90 (0.79–1.03)	0.73 (0.64–0.83)	0.66 (0.58–0.76)	<0.001
Model 3	1 [Reference]	0.90 (0.79–1.03)	0.74 (0.65–0.84)	0.67 (0.58–0.76)	<0.001
Lycopene
Range	<14.01	14.01–23.00	23.01–35.99	>35.99
No. deaths/total	1248/1857	817/1753	581/1718	367/1749
Model 1	1 [Reference]	0.79 (0.71–0.87)	0.66 (0.59–0.74)	0.61 (0.53–0.71)	<0.001
Model 2	1 [Reference]	0.82 (0.75–0.90)	0.74 (0.65–0.83)	0.74 (0.64–0.85)	<0.001
Model 3	1 [Reference]	0.82 (0.75–0.91)	0.73 (0.65–0.83)	0.74 (0.64–0.86)	<0.001
Lutein/zeaxanthin
Range	<12.60	12.60–17.99	18.00–25.20	>25.20
No. deaths/total	709/2093	743/2040	894/2130	1066/2127
Model 1	1 [Reference]	0.79 (0.68–0.91)	0.71 (0.63–0.80)	0.63 (0.55–0.72)	<0.001
Model 2	1 [Reference]	0.84 (0.73–0.96)	0.78 (0.69–0.87)	0.72 (0.63–0.83)	<0.001
Model 3	1 [Reference]	0.85 (0.74–0.97)	0.78 (0.69–0.88)	0.72 (0.63–0.83)	<0.001

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NHANES indicates National Health and Nutrition Examination Survey.

Model 1 was adjusted for age (continuous), sex (male or female), and race and ethnicity non‐Hispanic White (yes or no).

Model 2 was adjusted as model 1 plus education level (below high school, high school, or above high school), family poverty income ratio (<1.0, or ≥1.0), smoking status (never smoker, former smoker, or current smoker), drinking status (nondrinker, low‐to‐moderate drinker, or heavy drinker), body mass index (<25.0, 25.0–29.9, or >29.9), total energy intakes (in quartiles), physical activity (inactive, insufficiently active, or active), total cholesterol (in quartiles), high‐density lipoprotein cholesterol (in quartiles), estimated glomerular filtration rate (continuous), supplement use (yes or no), and self‐reported diabetes (yes or no).

Model 3 was adjusted as model 2 plus antihypertensive medication use (yes or no), systolic blood pressure (<120, 120–129, 130–139, or ≥140 mm Hg), and diastolic blood pressure (<70, 70–79, 80–89, or ≥90 mm Hg).

Restricted cubic splines was used to visualize dose–response relationships between the log2‐transformed carotenoids and the multivariable‐adjusted HRs of all‐cause mortality in hypertensive adults (Figure 1). Analyses showed that serum lycopene levels were linearly and negatively correlated with all‐cause mortality, whereas α‐carotene (P for nonlinearity=0.034), β‐carotene (P for nonlinearity <0.001), β‐cryptoxanthin (P for nonlinearity=0.042), and lutein/zeaxanthin (P for nonlinearity=0.039) were nonlinearly and negatively correlated with all‐cause mortality, with inflection points of 2.43, 8.49, 5.12, and 14.17 μg/dL, respectively.

Adjusted for age (continuous), sex (male or female), race and ethnicity non‐Hispanic White (yes or no), education level (below high school, high school, or above high school), family poverty income ratio (<1.0, or ≥1.0), smoking status (never smoker, former smoker, or current smoker), drinking status (nondrinker, low‐to‐moderate drinker, or heavy drinker), body mass index (<25.0, 25.0–29.9, or >29.9), total energy intakes (in quartiles), physical activity (inactive, insufficiently active, or active), total cholesterol (in quartiles), high‐density lipoprotein cholesterol (in quartiles), estimated glomerular filtration rate (continuous), supplement use (yes or no), self‐reported diabetes (yes or no), antihypertensive medication use (yes or no), systolic blood pressure (<120, 120–129, 130–139, or ≥140 mm Hg), and diastolic blood pressure (<70, 70–79, 80–89, or ≥90 mm Hg). HR indicates hazard ratio.

Associations Between the 5 Serum Carotenoids and Cardiovascular Mortality

During a median follow‐up period of 16.6 years, 1205 adult hypertensive individuals with cardiovascular death were identified. As shown in Table 3, compared with the reference quartile, quartiles 3 and 4 revealed a protective association of all 5 serum carotenoids with cardiovascular mortality in Model 1. However, with further adjustment for Model 2, serum β‐carotene and lutein/zeaxanthin were not associated with the risk of cardiovascular mortality. By adjusting Model 3, we found that compared with the lowest quartile, this association with the fourth quartile of serum carotenoids was evident for a reduced rate of cardiovascular mortality, with a 32% reduction for α‐carotene (HR, 0.68 [95% CI, 0.55–0.86], P _trend<0.001), a 29% reduction for β‐cryptoxanthin (HR, 0.71 [95% CI, 0.56–0.89], P _trend=0.001), and a 26% reduction for lycopene (HR, 0.74 [95% CI, 0.59–0.94], P _trend=0.011). In addition, we observed a significant association between the third quartile of lutein/zeaxanthin (HR, 0.74 [95% CI, 0.58–0.95]) and cardiovascular mortality compared with the first quartile after multivariate adjustment, whereas the fourth quartile of lutein/zeaxanthin was not. Similar results were observed in the associations of total serum carotenoid levels with cardiovascular mortality (Table S2). In addition, the restricted cubic splines results indicated that serum α‐carotene (P for nonlinearity=0.015), β‐cryptoxanthin (P for nonlinearity=0.014), and lutein/zeaxanthin (P for nonlinearity=0.020) concentrations showed nonlinear associations with cardiovascular mortality with inflection points of 2.31, 5.26, and 15.40 μg/dL, respectively (Figure 2).

Table 3.

Hazard Ratios (95% CIs) of Cardiovascular Mortality According to Quartiles of Serum Carotenoids Concentrations Among Hypertensive Adults in NHANES III and NHANES 2001–2006

	Serum carotenoids (μg/dL)
	Quartile 1	Quartile 2	Quartile 3	Quartile 4	P _trend
α‐Carotene
Range	<1.51	1.51–3.00	3.01–5.19	>5.19
No. deaths/total	185/2177	168/2195	199/2009	203/2009
Model 1	1 [Reference]	0.70 (0.56–0.88)	0.63 (0.53–0.74)	0.53 (0.43–0.64)	<0.001
Model 2	1 [Reference]	0.72 (0.57–0.90)	0.69 (0.58–0.83)	0.68 (0.54–0.85)	0.002
Model 3	1 [Reference]	0.72 (0.57–0.91)	0.70 (0.59–0.84)	0.68 (0.55–0.86)	0.002
β‐Carotene
Range	<8.01	8.01–14.19	14.20–24.99	>24.99
No. deaths/total	166/2196	149/2057	191/2065	249/2072
Model 1	1 [Reference]	0.81 (0.64–1.02)	0.74 (0.58–0.95)	0.67 (0.54–0.84)	<0.001
Model 2	1 [Reference]	0.87 (0.69–1.10)	0.90 (0.71–1.16)	0.89 (0.70–1.11)	0.412
Model 3	1 [Reference]	0.88 (0.70–1.12)	0.93 (0.73–1.18)	0.90 (0.72–1.14)	0.544
β‐Cryptoxanthin
Range	<5.00	5.00–7.99	8.00–12.69	>12.69
No. deaths/total	178/1922	200/2220	202/2127	175/2121
Model 1	1 [Reference]	0.73 (0.61–0.87)	0.61 (0.51–0.74)	0.56 (0.45–0.69)	<0.001
Model 2	1 [Reference]	0.80 (0.67–0.94)	0.70 (0.57–0.85)	0.70 (0.55–0.88)	0.001
Model 3	1 [Reference]	0.80 (0.67–0.95)	0.72 (0.59–0.88)	0.71 (0.56–0.89)	0.002
Lycopene
Range	<14.01	14.01–23.00	23.01–35.99	>35.99
No. deaths/total	291/1857	199/1753	120/1718	84/1749
Model 1	1 [Reference]	0.83 (0.68–1.02)	0.64 (0.50–0.81)	0.61 (0.49–0.76)	<0.001
Model 2	1 [Reference]	0.88 (0.73–1.05)	0.73 (0.57–0.93)	0.73 (0.58–0.91)	0.002
Model 3	1 [Reference]	0.88 (0.74–1.06)	0.73 (0.57–0.93)	0.74 (0.59–0.94)	0.004
Lutein/zeaxanthin
Range	<12.60	12.60–17.99	18.00–25.20	>25.20
No. deaths/total	137/2093	173/2040	197/2130	248/2127
Model 1	1 [Reference]	0.71 (0.56–0.89)	0.66 (0.53–0.82)	0.70 (0.57–0.87)	0.002
Model 2	1 [Reference]	0.75 (0.59–0.94)	0.73 (0.57–0.94)	0.79 (0.62–1.01)	0.091
Model 3	1 [Reference]	0.75 (0.60–0.94)	0.74 (0.58–0.95)	0.80 (0.63–1.02)	0.105

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NHANES indicates National Health and Nutrition Examination Survey.

Model 1 was adjusted for age (continuous), sex (male or female), and race and ethnicity non‐Hispanic White (yes or no).

Sensitivity Analyses

In sensitivity analyses, the negative association of serum carotenoid concentrations with the risk of all‐cause and cardiovascular mortality in the adjusted full model was not appreciably changed if adult hypertensive participants who died during the first 2 years of follow‐up were omitted (Table S3). Adjusting further for dietary covariates (intakes of total protein, total fat, cholesterol, fiber, and vitamins A, E, and C) or adjusting for serum nutritional biomarkers (iron, folate, and vitamin B12, A, E, and C levels) for the full model showed similar results (Table S4). Furthermore, compared with the lowest quartiles, the highest quartiles of dietary α‐carotene and β‐carotene intake were linked with lower risks of all‐cause mortality in hypertensive adults, whereas the highest quartiles of dietary β‐cryptoxanthin, lycopene, and lutein/zeaxanthin intake were not associated with the risk of all‐cause mortality (Table S5). Furthermore, the association of dietary carotenoid intakes (including α‐carotene, β‐carotene, β‐cryptoxanthin, lycopene, and lutein/zeaxanthin) with the risk of cardiovascular mortality has not been observed (Table S6).

Discussion

This prospective study investigates the relationship between 5 serum carotenoid concentrations and all‐cause and cardiovascular mortality in 8390 hypertensive adults over a median follow‐up time of 16.3 years. The findings of this study demonstrate that low serum α‐carotene, β‐carotene, β‐cryptoxanthin, lycopene, and lutein/zeaxanthin concentrations were associated with a higher risk of all‐cause and cardiovascular mortality in hypertensive adults. Multiple sensitivity analyses confirmed the robustness of our results.

“Oxidative stress” refers to an imbalance between oxidants and antioxidants that favors the oxidants, which may cause damage. ³⁵ Despite the fact that the association between oxidative stress and hypertension has been conclusively established in multiple animal models of hypertension, studies focusing on the inactivation of nitric oxide by superoxide, reactive oxygen species, and the corresponding signaling pathways in hypertension have shown various adverse outcomes. ³⁶ , ³⁷ , ³⁸ , ³⁹ In the pathogenesis of hypertension, these oxidative modifications could induce inflammasome activation, endothelial dysfunction, and endoplasmic reticular stress. Therefore, studies on the pathophysiology need to further evaluate these mechanical processes and pathways in human hypertension. ²⁹ , ⁴⁰

Carotenoids have been shown to reduce reactive oxygen species–induced damage, prevent lipid peroxidation, and be involved in cellular communications that regulate proliferation and apoptosis. ⁴¹ , ⁴² , ⁴³ Smokers and obese persons have been found to have lower serum carotenoid concentrations, ⁴⁴ , ⁴⁵ which may contribute to a greater mobilization of these antioxidants. ⁴⁶ , ⁴⁷ Both of these factors enhance chronic inflammation and oxidative stress. ⁴⁸ , ⁴⁹ Carotenoids, in addition, have the ability to shield cells and tissues from damage brought on by free radicals and singlet oxygen, which helps the immune system function more effectively. ⁵⁰ Carotenoids have demonstrated such significant antioxidation and anti‐inflammatory properties that the major carotenoids' antioxidant effects have been associated with several health benefits in various chronic diseases. ⁵¹ Studies have reported that carotenoids may delay the development of cancer and also decrease the risk of CVDs, osteoporosis, diabetes, as well as other pathological conditions. ¹² , ¹³ , ⁵² , ⁵³ , ⁵⁴ , ⁵⁵

Previous observational studies have examined the relationship between plasma or serum carotenoids and the risk of all‐cause and cardiovascular mortality. ⁸ , ⁹ , ¹⁵ , ¹⁶ , ¹⁷ , ¹⁸ , ¹⁹ , ²⁰ , ²¹ , ²² , ²³ , ²⁴ , ²⁵ , ⁵⁶ Despite inconsistent results, most of these studies found that different types of higher plasma or serum carotenoid concentrations were associated with a reduced risk of mortality. ¹⁵ , ¹⁶ , ¹⁷ , ¹⁸ , ¹⁹ , ²⁰ , ²¹ , ²² , ²³ , ²⁴ , ²⁵ Among them, lycopene, α‐carotene, and β‐carotene have been extensively studied as major antioxidants that exert a variety of bioactive effects on humans. In addition, a meta‐analysis of prospective studies summarized the association between plasma or serum carotenoid concentrations and the risk of all‐cause mortality. ²⁶ The results showed that compared with low concentrations, this association with the high blood carotenoids concentrations was evident for a reduced rate of all‐cause mortality, with a 25% reduction for total carotenoids (relative risk=0.75 [95% CI, 0.64–0.88]), a 24% reduction for α‐carotene (relative risk=0.76 [95% CI, 0.59–0.98]), and a 32% reduction for β‐carotene (relative risk=0.68 [95% CI, 0.55–0.83]), but not for lycopene and lutein/zeaxanthin. In addition, there was no significant association between blood β‐cryptoxanthin and all‐cause mortality in high and low analyses, while relative risk for each 15 μg/dL increase was 0.84 (95% CI, 0.76–0.94) in the continuous analysis.

However, the relationships between carotenoids and cardiovascular and all‐cause mortality in adult individuals are inconsistent. In a diabetic population, compared with the lowest quartile of serum β‐carotene (<148.4 nmol/L), the highest quartile (>424.9 nmol/L) was significantly linked with an increased risk of cardiovascular mortality (HR, 2.47 [95% CI, 1.62–3.76]). ⁹ Also, one meta‐analysis, including 6 randomized trials, demonstrated that β‐carotene supplementation might lead to an increased risk of cardiovascular mortality (HR, 1.1 [95% CI, 1.03–1.17]) compared with control treatment. ⁸ It should also be noted that the independent panel of the US Preventive Services Task Force even made an evidence‐based recommendation against using β‐carotene to prevent CVDs or cancer. ⁵⁷

Our study is among the first to examine the relationships between major serum carotenoids and the risk of all‐cause and cardiovascular mortality in a long‐term follow‐up epidemiological setting (median follow‐up period of 16.3 years). Our findings were based on a large, nationally representative sample of hypertensive adults in the United States, as well as a well‐characterized and relatively homogeneous study population, enabling appropriate control of the impact of confounding effects on study results. Numerous observational studies are limited by small sample sizes and short follow‐up periods, which reduces the reliability of the findings. In addition, the multiple potential confounders were carefully adjusted, including lifestyle, dietary and nutrient factors, BP and lipid levels, and antihypertensive medications. The low serum levels of α‐carotene, β‐carotene, β‐cryptoxanthin, lycopene, and lutein/zeaxanthin were all linked with an increase in the long‐term risk of both all‐cause mortality and cardiovascular mortality regardless of adjustments. In terms of the clinical significance and interpretation of our results, the findings of the current study were unaffected by artificial supplements and dietary nutrients. Also, the results of the sensitivity analyses further support the fact that the selected serum carotenoid levels might be nutrient biomarkers for the risk assessment of long‐term mortality and that the decreased levels of carotenoids call for the optimization of the dietary structure and actions against nutritional insufficiency.

However, several limitations should also be considered when interpreting these results. Although the serum carotenoid levels could represent the average daily intake, our results were based on a single assessment of carotenoid levels at baseline that did not reflect variations in serum carotenoid levels during the follow‐up period. In addition, the current study also lacked information on the course and severity of hypertension; despite this, the findings did not change much when other variables, such as ongoing antihypertensive therapy, were considered. Also, these results are based on US adults with hypertension, which may limit the generalizability of our findings to other populations, especially because a previous study in a diabetic population produced different results. Lastly, only the levels of 5 major serum carotenoids were analyzed in this study. Considering the complex in vivo metabolism of carotenoids, further studies should be considered.

Conclusions

In this nation‐based adult hypertensive population, we found that higher concentrations of major serum carotenoids, including α‐carotene, β‐carotene, β‐cryptoxanthin, lycopene, and lutein/zeaxanthin, were associated with a decreased risk of all‐cause and cardiovascular mortality. However, the results of this study should be interpreted with caution as the associations observed might be because of the combined effect of the antioxidants themselves and the intake of fruits and vegetables. Further studies are needed to validate our findings and explore the mechanism involved.

Sources of Funding

This work was supported by General Program of National Natural Science Foundation of China (81970339 to X.L. Li, 82270394 to H.F. Zhang, and 82200425 to R.R. Gao), The National High Technology Research and Development Program of China (2017YFC1700505 to X.L. Li), project from Gusu School (GSRCKY20210204 to H.F. Zhang), and Natural Science Foundation project of Jiangsu (BK20191072 to R.R. Gao). Dr X.L. Li and H.F. Zhang are Associate Fellows at the Collaborative Innovation Center for Cardiovascular Disease Translational Medicine.

Disclosures

The authors have no competing interests to declare.

Supporting information

Tables S1–S6

Figures S1–S2

Click here for additional data file.^{(618.6KB, pdf)}

Acknowledgments

The authors thank the participants and staff of the National Health and Nutrition Examination Survey (NHANES) III and NHANES 2001–2006 for their valuable contributions.

Supplemental Material is available at https://www.ahajournals.org/doi/suppl/10.1161/JAHA.122.027568

For Sources of Funding and Disclosures, see page 11.

Contributor Information

Haifeng Zhang, Email: haifeng_zhang@163.com.

Xinli Li, Email: xinli3267@njmu.edu.cn.

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49. Hosseini B, Saedisomeolia A, Allman‐Farinelli M. Association between antioxidant intake/status and obesity: a systematic review of observational studies. Biol Trace Elem Res. 2017;175:287–297. doi: 10.1007/s12011-016-0785-1 [DOI] [PubMed] [Google Scholar]
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55. Raposo MF, de Morais AM, de Morais RM. Carotenoids from marine microalgae: a valuable natural source for the prevention of chronic diseases. Mar Drugs. 2015;13:5128–5155. doi: 10.3390/md13085128 [DOI] [PMC free article] [PubMed] [Google Scholar]
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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Tables S1–S6

Figures S1–S2

Click here for additional data file.^{(618.6KB, pdf)}

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[jah38186-bib-0056] 56. Virtamo J, Pietinen P, Huttunen JK, Korhonen P, Malila N, Virtanen MJ, Albanes D, Taylor PR, Albert P. Incidence of cancer and mortality following alpha‐tocopherol and beta‐carotene supplementation: a postintervention follow‐up. JAMA. 2003;290:476–485. doi: 10.1001/jama.290.4.476 [DOI] [PubMed] [Google Scholar]

[jah38186-bib-0057] 57. Vitamin, Mineral, and multivitamin supplementation to prevent cardiovascular disease and cancer: Preventive medication. U.S. Preventive Services Task Force. Accessed July 3, 2022. Available at: https://www.uspreventiveservicestaskforce.org/uspstf/recommendation/vitamin‐supplementation‐to‐prevent‐cvd‐and‐cancer‐preventive‐medication [DOI] [PubMed]

PERMALINK

Associations of Serum Carotenoids With Risk of All‐Cause and Cardiovascular Mortality in Hypertensive Adults

Xu Zhu, MD

Iokfai Cheang, MD

Yuan Tang, MD

Mengsha Shi, MD

Qingqing Zhu, MD

Rongrong Gao, MD, PhD

Shengen Liao, MD

Wenming Yao, MD, PhD

Yanli Zhou, MD, PhD

Haifeng Zhang, MD, PhD

Xinli Li, MD, PhD

Abstract

Background

Methods and Results

Conclusions

Nonstandard Abbreviations and Acronyms

Clinical Perspective.

What Is New?

What Are the Clinical Implications?

Methods

Study Population

Definition of Hypertension

Measurement of Serum Carotenoid Levels

Outcome Variables

Covariate Analysis

Statistical Analysis

Results

Characteristics of the Study Participants

Table 1.

Detection Distributions and Correlations Between Serum Carotenoids

Associations Between the 5 Serum Carotenoids and All‐Cause Mortality

Table 2.

Figure 1. Restricted cubic spline analyses of the association of serum carotenoids (A: α‐carotene, B: β‐carotene, C: β‐cryptoxanthin, D: lycopene, and E: lutein/zeaxanthin) with all‐cause mortality.

Associations Between the 5 Serum Carotenoids and Cardiovascular Mortality

Table 3.

Figure 2. Restricted cubic spline analyses of the association of serum carotenoids (A: α‐carotene, B: β‐carotene, C: β‐cryptoxanthin, D: lycopene, and E: lutein/zeaxanthin) with cardiovascular mortality.

Sensitivity Analyses

Discussion

Conclusions

Sources of Funding

Disclosures

Supporting information

Acknowledgments

Contributor Information

REFERENCES

Associated Data

Supplementary Materials

ACTIONS

PERMALINK

RESOURCES

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