Abstract
To evaluate the association between plasma retinol levels with all‐cause mortality and investigate the possible effect modifiers in general hypertensive patients with no previous cardiovascular disease (CVD). This case‐control study was nested in the China Stroke Primary Prevention Trial (CSPPT), a randomized, double‐blind, controlled trial conducted in 32 communities in Anhui and Jiangsu provinces in China. The current study included 617 cases of all‐cause mortality and 617 controls matched on age (≤1 year), sex, treatment group, and study site. All‐cause mortality was the main outcome in this analysis, which included death due to any reason. The median follow‐up duration was 4.5 years. Overall, there was a U‐shaped relation of plasma retinol with all‐cause mortality. In the threshold effect analysis, the risk of all‐cause mortality significantly decreased with the increase in plasma retinol (per 10 μg/dL increments: OR, 0.73; 95% CI: 0.61‐0.87) in participants with plasma retinol <58.3 μg/dL and increased with the increase in plasma retinol (per 10 μg/dL increments: OR, 1.08; 95% CI: 1.01‐1.16) in those with plasma retinol ≥58.3 μg/L. In participants with plasma retinol <58.3 μg/dL, a stronger inverse association was observed in those with higher time‐averaged SBP (≥140 vs <140 mm Hg; P‐interaction = .034), or higher vitamin E levels (≥11.5 [quartile 4]; vs <11.5 μg/mL; P‐interaction = .013). The present study demonstrated that there was a U‐shaped relationship of plasma retinol levels with the risk of all‐cause mortality in general hypertensive patients, with a turning point around 58.3 μg/dL.
Keywords: all‐cause mortality, hypertension, retinol, systolic blood pressure, vitamin E
1. INTRODUCTION
Vitamin A is an essential liposoluble nutrient. It cannot be synthesized by the human body and must therefore be derived from either animal foods (meat, cheese, margarine, and dairy products) or carotenoids from plant‐based foods. In plasma, vitamin A circulates as retinol, which is the most commonly used indicator of vitamin A status. 1 Retinol has an important role in maintaining mammalian health and is involved in various physiologic processes, including vision, reproduction, epithelial integrity, cell differentiation and proliferation and immune function. 2 , 3
Accordingly, it is feasible to hypothesize that retinol might be of importance for prevention of early mortality. A recent meta‐analysis of 18 randomized trials found that vitamin A supplementation was associated with a 12% reduction in all‐cause mortality (RR, 0.88; 95% CI: 0.83, 0.93) in children aged six months to 5 years. 4 By contrast, a recent fixed‐effect model meta‐analysis of randomized trials, which excluded those trials with children and pregnant women, reported a harmful effect of vitamin A on all‐cause mortality in trials with a low risk of bias (RR, 1.11; 95% CI: 1.05, 1.16). 5 Prior randomized trials mainly examined the effects of relatively high vitamin A supplementation in high risk subjects, rather than the effects of dietary vitamin A derived from foods in general populations. In fact, the prospective relation of plasma retinol with the risk of mortality is still inconclusive. Some previous studies have found an inverse association between plasma retinol and risk of mortality, 6 , 7 , 8 , 9 while others have shown no evidence of an association between plasma retinol and mortality. 10 Nevertheless, two studies utilizing data from the same database suggested that plasma retinol has a U‐shaped association with all‐cause and cardiovascular disease mortality (The Third National Health and Nutrition Examination Survey, NHANES III). 11 , 12
Hypertension is one of important risk factors for vascular complications and mortality. 13 , 14 It affects over one billion adults worldwide and is a serious public health challenge. Moreover, many hypertensive patients have no previous history of cardiovascular disease. 15 However, no previous study has investigated the association of plasma retinol with all‐cause mortality in general hypertensive patients.
These inconsistent findings and the remaining questions regarding the association between plasma retinol and all‐cause mortality were the motivation behind the current study. Using data from the China Stroke Primary Prevention Trial (CSPPT), 16 we aimed to investigate the association between plasma retinol levels and all‐cause mortality using a nested case‐control design. Furthermore, we also examine the possible effect modifiers on the retinol and all‐cause mortality association, which no previous study has yet thoroughly evaluated.
2. METHODS
2.1. Study population
The current nested case‐control study is a post hoc analysis, and sample of participants was drawn from the CSPPT. The trial design, protocol, and major results of the CSPPT have been previously described in detail. 16 Briefly, CSPPT was a randomized, double‐blind, controlled trial conducted in 32 communities in China from May 19, 2008, to August 24, 2013. Eligible participants were men and women aged 45‐75 years with hypertension, defined as seated resting systolic blood pressure (SBP) ≥140 mm Hg or diastolic blood pressure (DBP) ≥90 mm Hg at both the screening and recruitment period or recently took antihypertensive drugs. The major exclusion criteria included history of physician‐diagnosed stroke, myocardial infarction (MI), heart failure, post‐coronary revascularization, and/or congenital heart disease. The CSPPT was registered with ClinicalTrials.gov, NCT00794885.
2.2. Intervention and follow‐up
Eligible participants were randomly assigned to a double‐blind treatment of daily enalapril 10 mg and folate 0.8 mg or enalapril 10 mg alone.
All participants were scheduled for follow‐up every 3 months. At each follow‐up visit, vital signs, study drug adherence, concomitant medication use, adverse events, and potential end point events were recorded by trained researchers and physicians.
Time‐averaged on‐treatment SBP or DBP was calculated for each participant using all post baseline results up to the exit visit (number of BP measurements during the treatment period: median, 16; interquartile range [IQR], 12‐18).
2.3. Study outcomes
All‐cause mortality, a prespecified end point of the CSPPT, was the primary outcome in this analysis. All‐cause mortality included mortality due to any reason. Evidence for mortality included death certificates from hospitals or report of the investigator after visiting.
Secondary outcomes included death from cardiovascular disease (CVD) includes sudden cardiac death, death due to MI, heart failure, stroke, or cardiovascular invasive procedures, death due to cardiovascular hemorrhage, and death due to other known vascular causes, and death from cancer includes death as a direct result of cancer, or from a complication of cancer, or from withdrawal of other therapies due to concerns relating to the poor prognosis associated with the cancer.
All the study outcomes were reviewed and adjudicated by an independent Endpoint Adjudication Committee, whose members were unaware of study‐group assignments.
2.4. Nested case‐control study
During a median treatment duration of 4.5 years, all‐cause mortality occurred in 302 participants (2.9%) in the enalapril‐folic acid group as compared to 320 participants (3.1%) in the enalapril group (HR, 0.94; 95% CI, 0.81‐1.10; P = .47).
Using data from the CSPPT, we established a nested case‐control study with 622 incident cases and 622 matched controls within this cohort. Controls were randomly chosen from the baseline CSPPT participants who were alive during the follow‐up and were matched for age (≤1 year), sex, treatment group, and study site with the cases on a 1:1 ratio. Two cases and three controls with missing data on plasma retinal levels and their paired individuals (two controls and three cases) were excluded; therefore, 617 nested case‐control pairs were included in the final analysis (Figure S1).
The parent study (CSPPT) and this study were approved by the Ethics Committee of the Institute of Biomedicine, Anhui Medical University, Hefei, China (FWA assurance number: FWA00001263). All participants provided written informed consent.
2.5. Laboratory assays
Serum vitamin B12 and folate were measured by a commercial laboratory using a chemiluminescent immunoassay (New Industrial). Serum total homocysteine (tHcy), glucose, and lipids levels were measured using automatic clinical analyzers (Beckman Coulter) at the core laboratory of the National Clinical Research Center for Kidney Disease, Nanfang Hospital, Guangzhou, China. Plasma retinol, vitamin E, and vitamin D were measured by liquid chromatography with tandem quadrupole mass spectrometry (LC‐MS/MS) in a commercial laboratory (Beijing DIAN Medical Laboratory). Both intra‐assay and inter‐assay coefficients of variation (CV) for duplicate samples (randomly placed among the study samples) were calculated. The intra‐assay CV of plasma retinol, vitamin E, and vitamin D were ranged from 0.25% to 15.12%, 0.25% to 16.95%, and 0.14% to 13.77%, while the inter‐assay CV were ranged from 4.66% to 6.40%, 3.97% to 5.02%, and 4.54% to 7.01%, respectively.
2.6. Statistical analysis
Baseline characteristics were presented as mean (standard deviation, SD) or median (IQR) for continuous variables and proportions for categorical variables.
Odds ratios (ORs) and 95% confidence intervals (95% CIs) for all‐cause mortality in relation to plasma retinol levels were calculated using conditional logistic regression models, without and with adjustment for age, sex, body mass index (BMI), methylenetetrahydrofolate reductase (MTHFR) C677T genotypes, smoking and alcohol drinking status, systolic blood pressure (SBP), diastolic blood pressure (DBP), fasting blood glucose, total cholesterol (TC), folate, total homocysteine (tHcy), vitamin D, vitamin E, estimated glomerular filtration rate (eGFR) at baseline, as well as mean SBP and DBP during the treatment period. We applied two‐piecewise regression models to examine the threshold effect of plasma retinol on all‐cause mortality using a smoothing function. Likelihood‐ratio tests and bootstrap resampling methods were used to determine the threshold level (turning point).
As additional exploratory analyses, possible modifications of the relation of all‐cause mortality with plasma retinol were also assessed for variables including sex, age (<60 vs ≥60 years), BMI (<24 vs ≥24 kg/m2), SBP (<160 vs ≥160 mm Hg), treatment group (enalapril vs enalapril‐folic acid), TC (<5.2 vs ≥5.2 mmol/L), folate (<7.8 [median] vs ≥7.8 ng/mL), tHcy (<14 [median] vs ≥14 µmol/L), vitamin B12 (<385 [median] vs. ≥385 μg/mL), fasting blood glucose (<6.1 vs ≥6.1 mmol/L or diabetes), vitamin D (<19.8 [median] vs ≥19.8 ng/mL), and vitamin E (<11.5 [quartile 4] vs ≥11.5 μg/mL) levels at baseline and mean SBP (<140 vs ≥140 mm Hg) during the treatment period. Diabetes was defined as fasting serum glucose ≥7.0 mmol/L or self‐reported use of hypoglycemic agents or insulin, or physician‐diagnosed diabetes.
A two‐tailed P < .05 was considered to be statistically significant in all analyses. R software (http://www.R‐project.org) and Empower (R) (www.empowerstats.com, X&Y Solutions, Inc) were used for all statistical analyses.
3. RESULTS
3.1. Characteristics of study participants
A total of 617 pairs (matched individuals) were included in the current analysis (Figure S1). Baseline characteristics of cases and control subjects are shown in Table 1. The mean age of all participants was 64.6 years (SD, 7.3). The median plasma retinol concentration was 66.2 μg/dL (IQR, 51.5, 82.8). Mortality cases tended to have higher fasting glucose and tHcy and lower BMI, vitamin D, and eGFR levels at baseline, as well as higher SBP and DBP levels during the treatment period, compared to control subjects. Furthermore, plasma retinol levels were positively associated with current smoking, alcohol drinking, male sex, TC, TG, HDL‐C, SBP, DBP, vitamin B12, tHcy, vitamin E and vitamin D levels, and glucose‐lowering drugs usage at baseline, as well as DBP levels during the treatment period, and were inversely associated with age and eGFR levels at baseline (Table S1).
TABLE 1.
Characteristics of cases and controls a
| Characteristic | Total | Cases | Controls | P value |
|---|---|---|---|---|
| N | n = 1234 | n = 617 | N = 617 | |
| Age, y | 64.6 ± 7.3 | 64.6 ± 7.3 | 64.6 ± 7.3 | .982 |
| Male, No. (%) | 724 (58.7) | 362 (58.7) | 362 (58.7) | |
| Body mass index, kg/m2 | 23.8 ± 3.7 | 23.6 ± 3.8 | 24.0 ± 3.6 | .042 |
| Enalapril‐folic acid group | 604 (48.9) | 302 (48.9) | 302 (48.9) | |
| Current smoking, No. (%) | 431 (35.0) | 218 (35.4) | 213 (34.5) | .749 |
| Current drinking, No. (%) | 392 (31.8) | 185 (30.0) | 207 (33.5) | .185 |
| MTHFR genotypes, No. (%) | ||||
| CC | 351 (28.4) | 171 (27.7) | 180 (29.2) | .311 |
| CT | 584 (47.3) | 285 (46.2) | 299 (48.5) | |
| TT | 299 (24.2) | 161 (26.1) | 138 (22.4) | |
| BP mean (SD), mm Hg | ||||
| Systolic BP at baseline | 168.7 ± 21.2 | 169.7 ± 22.0 | 167.8 ± 20.3 | .119 |
| Diastolic BP at baseline | 92.5 ± 12.7 | 92.8 ± 13.0 | 92.3 ± 12.4 | .478 |
| Time‐averaged systolic BP | 142.3 ± 13.1 | 144.6 ± 14.7 | 140.0 ± 10.7 | <.001 |
| Time‐averaged diastolic BP | 82.1 ± 8.7 | 83.2 ± 9.5 | 81.1 ± 7.8 | <.001 |
| Laboratory results | ||||
| Total cholesterol, mmol/L | 5.4 ± 1.2 | 5.4 ± 1.2 | 5.5 ± 1.2 | .294 |
| Triglyceride, mmol/L b | 1.3 (1, 1.8) | 1.3 (1, 1.8) | 1.3 (1, 1.8) | .552 |
| HDL‐C, mmol/L | 1.4 ± 0.4 | 1.4 ± 0.4 | 1.4 ± 0.4 | .617 |
| Fasting glucose, mmol/L | 5.8 ± 1.9 | 6.0 ± 2.3 | 5.6 ± 1.4 | <.001 |
| eGFR, mL/min/1.73my | 88.1 ± 15.4 | 87.3 ± 17.5 | 89.0 ± 13.0 | .053 |
| Vitamin B12, pg/mL | 417.7 ± 164.5 | 419.3 ± 172.7 | 416.1 ± 156.1 | .733 |
| Total homocysteine, μmol/L b | 14 (11.5,17.7) | 14.3 (11.7,18.5) | 13.7 (11.4,17) | .019 |
| Folate, ng/mL b | 7.8 (5.3, 10.5) | 7.8 (5.2, 10.4) | 8.0 (5.4, 10.6) | .714 |
| Retinol, μg/dL b | 66.2 (51.5, 82.8) | 66.4 (50.6, 84.5) | 66.1 (53.1, 81.6) | .553 |
| Vitamin E, μg/mL b | 9.1 (7.2, 11.5) | 9 (7.2, 11.4) | 9.2 (7.3, 11.5) | .493 |
| Vitamin D, ng/mL b | 19.8 (14.0, 26.0) | 19.2 (13.2, 25.1) | 20.5 (14.9, 26.8) | .004 |
| Medication use. No. (%) | ||||
| Antiplatelet drugs | 32 (2.6) | 13 (2.1) | 19 (3.1) | .283 |
| Lipid‐lowering drugs | 7 (0.6) | 4 (0.6) | 3 (0.5) | .705 |
| Glucose‐lowering drugs | 30 (2.4) | 17 (2.8) | 13 (2.1) | .460 |
| Antihypertensive drugs | 565 (45.8) | 286 (46.4) | 279 (45.2) | .689 |
Abbreviations: BP, blood pressure; eGFR, estimated glomerular filtration rate; HDL‐C, high‐density lipoprotein cholesterol; MTHFR, methylenetetrahydrofolate reductase.
Continuous variables are presented as mean ± SD.
Variables are presented as median (interquartile range).
3.2. Association of plasma retinol with the risk of all‐cause mortality
Overall, there was a U‐shaped relationship of plasma levels of retinol and all‐cause mortality (Figure 1). In the threshold effect analysis, the risk of all‐cause mortality significantly decreased with the increase in plasma retinol (per 10 μg/dL increments: OR, 0.73; 95% CI: 0.61, 0.87) in participants with plasma retinol <58.3 μg/dL and increased with the increment of plasma retinol (per 10 μg/dL increments: OR, 1.08; 95% CI: 1.01, 1.16) in participants with plasma retinol ≥58.3 μg/dL (Table 2). Accordingly, compared to control subjects, mortality cases had significantly lower retinol levels in participants with plasma retinol <58.3 μg/dL and higher retinol levels in participants with plasma retinol ≥58.3 μg/dL (Table S2).
FIGURE 1.
The association between plasma retinol and risk of all‐cause mortality*. *Adjusted for age, sex, treatment group, study centers, MTHFR C677T genotypes, body mass index (BMI), smoking, alcohol drinking, systolic blood pressure (SBP), diastolic blood pressure (DBP), fasting blood glucose, total cholesterol (TC), folate, total homocysteine (tHcy), vitamin D, vitamin E, estimated glomerular filtration rate (eGFR) at baseline, as well as mean SBP and DBP during the treatment period
TABLE 2.
Threshold effect analyses of retinol levels (per 10 μg/dL increment) on the risk of all‐cause mortality using two‐piecewise regression models a
| Retinol μg/dL | Cases/Controls | Crude models | Retinol μg/dL | Cases/Controls | Adjusted models | ||
|---|---|---|---|---|---|---|---|
| OR (95% CI) | P value | OR (95% CI) | P value | ||||
| <49.5 | 147/120 | 0.65 (0.51, 0.83) | <.001 | <58.3 | 235/220 | 0.73 (0.61, 0.87) | <.001 |
| ≥49.5 | 470/497 | 1.06 (1.00, 1.11) | .038 | ≥58.3 | 382/397 | 1.08 (1.01, 1.16) | .031 |
Adjusted for age, sex, body mass index (BMI), MTHFR C677T genotypes, smoking, alcohol drinking, systolic blood pressure (SBP), diastolic blood pressure (DBP), fasting blood glucose, total cholesterol (TC), folate, total homocysteine (tHcy), estimated glomerular filtration rate (eGFR), vitamin D, vitamin E, as well as mean SBP and DBP during the treatment period.
A similar U‐shaped trend was found for cancer mortality. However, there was a non‐significant inverse relation of plasma retinol levels with CVD mortality (Figure S2).
3.3. Stratified analyses
Stratified analyses were conducted to evaluate the relationship of plasma retinol (per 10 μg/dL increment) with the risk of all‐cause mortality by turning point (58.3 μg/dL) in various subgroups (Figure 2 and Table S3).
FIGURE 2.
The association between plasma retinol levels (per 10 μg/dL increments) and risk of all‐cause death by turning point (Retinol; 58.3 μg/dL) in various subgroups*. *Adjusted for age, sex, treatment group, study centers, MTHFR C677T genotypes, body mass index (BMI), smoking, alcohol drinking, systolic blood pressure (SBP), diastolic blood pressure (DBP), fasting blood glucose, total cholesterol (TC), folate, total homocysteine (tHcy), estimated glomerular filtration rate(eGFR), vitamin D, vitamin E at baseline, as well as mean SBP and DBP during the treatment period. #Diabetes was defined as fasting serum glucose ≥7.0 mmol/L or self‐reported use of hypoglycemic agents or insulin, or physician‐diagnosed diabetes
In participants with plasma retinol <58.3 μg/dL, a stronger inverse relation of plasma retinol with all‐cause mortality was observed in those with higher time‐averaged SBP (≥140 mm Hg; OR, 0.55; 95% CI: 0.39‐0.77; vs <140 mm Hg; OR, 0.90; 95% CI: 0.64‐1.25; P for interaction = .034) or higher vitamin E levels (≥11.5 μg/dL [quartile 4]; OR, 0.15; 95% CI: 0.04‐0.64; vs <11.5 μg/dL; OR, 0.74; 95% CI: 0.58‐0.94; P for interaction = .013).
None of the other stratified variables significantly modified the relation of plasma retinol with all‐cause mortality in participants with plasma retinol <58.3 or ≥58.3 μg/dL (P for all interactions >.05).
4. DISCUSSION
In this nested case‐control study, we observed a U‐shaped relationship of plasma retinol with the risk of all‐cause mortality among a Chinese hypertensive population, and revealed a turning point (58.3 μg/dL for plasma retinol) by threshold effect analysis.
The association between plasma retinol and mortality risk has been previously examined in several studies; however, the findings are inconsistent. Espe et al, 17 Bataille et al, 18 and Kalousová et al 8 suggested that decreased retinol is associated with increased mortality risk in hemodialysis patients. Connolly et al 7 found that a lower retinol level was an independent predictor of all‐cause mortality. This is supported by Formelli et al 19 who showed that low plasma retinol strongly predicted breast cancer death in postmenopausal breast cancer patients and De Keyser et al 9 who demonstrated that a higher serum vitamin A concentration was related to decreased mortality in ischemic stroke patients. Additionally, Brazionis et al found that plasma retinol was inversely associated with CVD mortality in well‐nourished Australian adults. 6 Interestingly, Fletcher et al 10 found no obvious relationship of plasma retinol with all‐cause and cardiovascular disease mortality among 1214 participants aged 75‐84 years. Moreover, Goyal et al 11 reported U‐shaped associations between serum vitamin A (quintiles) and all‐cause and CVD mortality in adults of the NHANES III. Using the same database (NHANES III), a recent study suggested that serum vitamin A levels that are either lower than 30 mg/dL or greater than 80 mg/dL were associated with a high risk of subsequent mortality. 12 Such inconsistent findings may be due to differences in population characteristics or study outcomes. Moreover, of note, none of the above studies thoroughly evaluated the possible effect modifiers.
Our current study provides two new insights into this field. First, a U‐shaped relationship was found between plasma retinol levels and all‐cause mortality in general hypertensive patients with no major cardiovascular diseases. Retinol may have a direct on the regulation of cell growth, differentiation, and apoptosis. 20 , 21 Moreover, some in vitro studies have reported an advantageous effect of retinoids on oxidative stress, inflammation, and endothelial function. 22 , 23 These results may possibly explain the inverse relationship of plasma retinol with mortality in study participants with relatively lower retinol levels. However, retinol may be a double‐edged sword. It has been reported that high retinol levels may contribute as an additional factor to the oxidative damage. 24 Elevated retinol levels have also been related to embryonic malformations and can cause damage to the mineral density, bone, skin, internal organs, and the nervous system. 25 , 26 In addition, retinol and its derivatives have been known to alter mitochondrial structure and function by causing swelling of the organelle. 27 Mitochondrial dysfunction has also been known to cause bioenergy disorders, increased reactive oxygen species, and apoptosis or necrosis. 27 Of note, we found a non‐significant inverse relation of plasma retinol levels with CVD mortality. The possible explanations include, first, the range of the retinol levels in our current study was not wide enough to find the significant plasma retinol and CVD mortality association. Second, we did not have enough sample size for the analysis. Overall, our findings were just hypothesis generating. More studies are needed to verify this hypothesis and further investigate the underlying mechanisms.
Second, the BP levels during the treatment period and the vitamin E levels appear to have modified the inverse relation of plasma retinol with the risk of all‐cause mortality among participants with plasma retinol <58.3 μg/L. A greater inverse relationship between plasma retinol and all‐cause mortality was observed in those with higher time‐averaged SBP or higher vitamin E levels. One possible mechanism linking high BP and increased risk of all‐cause mortality is endothelial dysfunction. 28 Patients with higher BP typically have impaired endothelial function, which is largely associated with diminished bioactivity of nitric oxide (NO). 29 Plasma retinol may directly improve endothelial dysfunction 21 and therefore produce greater beneficial effect among those with higher treated BP levels. It is generally accepted that vitamin E is one of the major fat‐soluble antioxidants which can aid in reducing the extent of lipid peroxidation, oxidative stress, and DNA damage. 30 We speculate that vitamin E and retinol levels may jointly maintain total health by different mechanisms. Our results and hypotheses need to be further confirmed in future studies.
Our study has several limitations. Frist, plasma retinol concentrations were only measured at baseline. More frequent measurements of the plasma retinol could have provided more useful information. Second, our current study was conducted in a Chinese hypertensive population. Whether the observed findings can be extrapolated to other populations will require further investigation. Third, although a number of potential confounders had been adjusted, it is possible that the result could be affected by unmeasured or unidentified factors. Finally, our study was underpowered for assessing the risk of specific causes of mortality. As such, more studies, including intervention trials, are needed to confirm our findings and further evaluate the risks or benefits of plasma retinol levels on the risk of mortality.
5. CONCLUSIONS
Our study found a U‐shaped relationship of plasma retinol and the risk of all‐cause mortality among hypertensive adults, with a turning point around 58.3 μg/dL. Overall, our findings provide some new information regarding the benefit‐risk ratio of vitamin A supplementation and mortality risk in hypertensive patients. If further confirmed, our results would offer a novel strategy to modulate mortality risk by optimizing individual blood retinol levels.
CONFLICT OF INTEREST
Dr Xiping Xu reports grants from the National Key Research and Development Program [2016YFE0205400, 2018ZX09739010, 2018ZX09301034003], the Science and Technology Planning Project of Guangzhou, China [201707020010], the Science, Technology and Innovation Committee of Shenzhen [JSGG20170412155639040, GJHS20170314114526143], and the Economic, Trade and Information Commission of Shenzhen Municipality [20170505161556110, 20170505160926390]. Dr Xianhui Qin reports grants from the National Natural Science Foundation of China [81730019] and Outstanding Youths Development Scheme of Nanfang Hospital, Southern Medical University [2017J009]. Dr Huiyuan Guo reports grants from the 111 project from the Education Ministry of China [No. B18053].
AUTHORS' CONTRIBUTIONS
Huan Li, Xiping Xu, Xianhui Qin, and Hao Zhang designed the research; Huan Li and Chengzhang Liu analyzed data; Huan Li, Xianhui Qin and Xiaobin Wang wrote the paper; Binyan Wang, Jianping Li, Yan Zhang, Yong Huo, Xiaobin Wang, and Xianhui Qin contributed to data collection; all authors reviewed/edited the manuscript important intellectual content, and read and approved the final manuscript.
Supporting information
Appendix S1
ACKNOWLEDGMENTS
We are grateful to all study participants for their cooperation.
Li H, He P, Lin T, et al. Association between plasma retinol levels and the risk of all‐cause mortality in general hypertensive patients: A nested case‐control study. J Clin Hypertens. 2020;22:906–913. 10.1111/jch.13866
Xiping Xu, Xianhui Qin and Hao Zhang contributed equally to this work.
Funding information
The study was supported by funding from the following: the National Key Research and Development Program [2016YFE0205400, 2018ZX09739, 2018ZX093010 34003]; the National Natural Science Foundation of China [81730019, 81973133]; the Science and Technology Planning Project of Guangzhou, China [201707020010]; the Science, Technology and Innovation Committee of Shenzhen [JSGG20170412155639 040, GJHS20170314114526143]; the Economic, Trade and Information Commission of Shenzhen Municipality [20170505161556110, 20170505160926390]; and the Outstanding Youths Development Scheme of Nanfang Hospital, Southern Medical University [2017J009].
Contributor Information
Hao Zhang, Email: zhanghaocau@cau.edu.cn.
Xiping Xu, Email: xipingxu126@126.com.
Xianhui Qin, Email: pharmaqin@126.com.
REFERENCES
- 1. Liden M, Eriksson U. Understanding retinol metabolism: structure and function of retinol dehydrogenases. J Biol Chem. 2006;281(19):13001‐13004. [DOI] [PubMed] [Google Scholar]
- 2. Czarnewski P, Das S, Parigi SM, Villablanca EJ. Retinoic acid and its role in modulating intestinal innate immunity. Nutrients. 2017;9(1):68. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3. Bar‐El DS, Reifen R. Vitamin A and the epigenome. Crit Rev Food Sci Nutr. 2017;57(11):2404‐2411. [DOI] [PubMed] [Google Scholar]
- 4. Imdad A, Mayo‐Wilson E, Herzer K, Bhutta ZA. Vitamin A supplementation for preventing morbidity and mortality in children from six months to five years of age. Cochrane Database Syst Rev. 2017;3:D8524. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5. Bjelakovic G, Nikolova D, Gluud LL, Simonetti RG, Gluud C. Antioxidant supplements for prevention of mortality in healthy participants and patients with various diseases. Cochrane Database Syst Rev. 2012;3:D7176. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6. Brazionis L, Walker KZ, Itsiopoulos C, O'Dea K. Plasma retinol: a novel marker for cardiovascular disease mortality in Australian adults. Nutr Metab Cardiovasc Dis. 2012;22(10):914‐920. [DOI] [PubMed] [Google Scholar]
- 7. Connolly GM, Cunningham R, Maxwell AP, Young IS. Decreased serum retinol is associated with increased mortality in renal transplant recipients. Clin Chem. 2007;53(10):1841‐1846. [DOI] [PubMed] [Google Scholar]
- 8. Kalousova M, Kubena AA, Kostirova M, et al. Lower retinol levels as an independent predictor of mortality in long‐term hemodialysis patients: a prospective observational cohort study. Am J Kidney Dis. 2010;56(3):513‐521. [DOI] [PubMed] [Google Scholar]
- 9. De Keyser J, De Klippel N, Merkx H, Vervaeck M, Herroelen L. Serum concentrations of vitamins A and E and early outcome after ischaemic stroke. Lancet. 1992;339(8809):1562‐1565. [DOI] [PubMed] [Google Scholar]
- 10. Fletcher AE, Breeze E, Shetty PS. Antioxidant vitamins and mortality in older persons: findings from the nutrition add‐on study to the Medical Research Council Trial of Assessment and Management of Older People in the Community. Am J Clin Nutr. 2003;78(5):999‐1010. [DOI] [PubMed] [Google Scholar]
- 11. Goyal A, Terry MB, Siegel AB. Serum antioxidant nutrients, vitamin A, and mortality in U.S. Adults. Cancer Epidemiol Biomarkers Prev. 2013;22(12):2202‐2211. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12. Min KB, Min JY. Relation of serum vitamin A levels to all‐cause and cause‐specific mortality among older adults in the NHANES III population. Nutr Metab Cardiovasc Dis. 2014;24(11):1197‐1203. [DOI] [PubMed] [Google Scholar]
- 13. He M, Qin X, Cui Y, et al. Prevalence of unrecognized lower extremity peripheral arterial disease and the associated factors in Chinese hypertensive adults. Am J Cardiol. 2012;110(11):1692‐1698. [DOI] [PubMed] [Google Scholar]
- 14. Fan F, Yuan Z, Qin X, et al. Optimal systolic blood pressure levels for primary prevention of stroke in general hypertensive adults: findings from the CSPPT (China Stroke Primary Prevention Trial). Hypertension. 2017;69(4):697‐704. [DOI] [PubMed] [Google Scholar]
- 15. Franklin SS, Jacobs MJ, Wong ND, L'Italien GJ, Lapuerta P. Predominance of isolated systolic hypertension among middle‐aged and elderly US hypertensives: analysis based on National Health and Nutrition Examination Survey (NHANES) III. Hypertension. 2001;37(3):869‐874. [DOI] [PubMed] [Google Scholar]
- 16. Huo Y, Li J, Qin X, et al. Efficacy of folic acid therapy in primary prevention of stroke among adults with hypertension in China: the CSPPT randomized clinical trial. JAMA. 2015;313(13):1325‐1335. [DOI] [PubMed] [Google Scholar]
- 17. Espe KM, Raila J, Henze A, et al. Impact of vitamin A on clinical outcomes in haemodialysis patients. Nephrol Dial Transplant. 2011;26(12):4054‐4061. [DOI] [PubMed] [Google Scholar]
- 18. Bataille S, Landrier JF, Astier J, et al. Plasma retinol concentration is mainly driven by transthyretin in hemodialysis patients. J Ren Nutr. 2017;27(6):395‐401. [DOI] [PubMed] [Google Scholar]
- 19. Formelli F, Meneghini E, Cavadini E, et al. Plasma retinol and prognosis of postmenopausal breast cancer patients. Cancer Epidemiol Biomarkers Prev. 2009;18(1):42‐48. [DOI] [PubMed] [Google Scholar]
- 20. Gudas LJ, Wagner JA. Retinoids regulate stem cell differentiation. J Cell Physiol. 2011;226:322‐330. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21. Altucci L, Gronemeyer H. The promise of retinoids to fight against cancer. Nat Rev Cancer. 2001;1:181‐193. [DOI] [PubMed] [Google Scholar]
- 22. Palace VP, Khaper N, Qin Q, Singal PK. Antioxidant potentials of vitamin a and carotenoids and their relevance to heart disease. Free Radic Biol Med. 1999;26:746‐761. [DOI] [PubMed] [Google Scholar]
- 23. Achan V, Tran CT, Arrigoni F, Whitley GS, Leiper JM, Vallance P. All‐trans‐retinoic acid increases nitric oxide synthesis by endothelial cells: a role for the induction of dimethylarginine dimethylaminohydrolase. Circ Res. 2002;90(7):764‐769. [DOI] [PubMed] [Google Scholar]
- 24. Roehrs M, Valentini J, Bulcao R, et al. The plasma retinol levels as pro‐oxidant/oxidant agents in haemodialysis patients. Nephrol Dial Transplant. 2009;24(7):2212‐2218. [DOI] [PubMed] [Google Scholar]
- 25. Michaelsson K, Lithell H, Vessby B, Melhus H. Serum retinol levels and the risk of fracture. N Engl J Med. 2003;348(4):287‐294. [DOI] [PubMed] [Google Scholar]
- 26. Colbert MC. Retinoids and cardiovascular developmental defects. Cardiovasc Toxicol. 2002;2(1):25‐39. [DOI] [PubMed] [Google Scholar]
- 27. de Oliveira MR. Vitamin A and retinoids as mitochondrial toxicants. Oxid Med Cell Longev. 2015;2015:140267. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28. Matsuzawa Y, Kwon TG, Lennon RJ, Lerman LO, Lerman A. Prognostic value of flow‐mediated vasodilation in brachial artery and fingertip artery for cardiovascular events: a systematic review and meta‐analysis. J Am Heart Assoc. 2015;4(11):e002270. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 29. Panza JA, Garcia CE, Kilcoyne CM, Quyyumi AA, Cannon RR. Impaired endothelium‐dependent vasodilation in patients with essential hypertension. Evidence that nitric oxide abnormality is not localized to a single signal transduction pathway. Circulation. 1995;91(6):1732‐1738. [DOI] [PubMed] [Google Scholar]
- 30. Zhang D, Okada S, Yu Y, Zheng P, Yamaguchi R, Kasai H. Vitamin E inhibits apoptosis, DNA modification, and cancer incidence induced by iron‐mediated peroxidation in Wistar rat kidney. Cancer Res. 1997;57(12):2410‐2414. [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Appendix S1