The present chapter aims to examine the effect of dietary vitamin D intake on CVD events and all-cause mortality in epidemiological study- evidence from Caerphilly Cohort.
JG, JAL, DIG designed the study; JG conducted the research and wrote the manuscript. JRC, PCE and JEP contributed to the interpretation of the findings.
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Vitamin D intake and risk of cardiovascular diseases and all-cause mortality: evidence from the Caerphilly Prospective Study
Jing Guo, John R Cockcroft, Peter C Elwood, Janet E Pickering, Julie A Lovegrove and David I Givens
1 From the Institute for Food, Nutrition and Health (JG, JAL, DIG, JEP), the Hugh Sinclair Unit of Human Nutrition (JAL) and the Institute for Cardiovascular and Metabolic Research (JG, DIG, JAL) University of Reading, Reading, RG6 6AR, United Kingdom; Wales Heart Research Institute (JRC), andDepartment of Primary Care and Public Health (PCE), Cardiff University, United Kingdom.
2 Address correspondences to Jing Guo, E-mail: [email protected]. 3 Supported by the Barham Benevolent Foundation.
4Abbreviations used: CVD, cardiovascular disease; MI, myocardial infarction; systolic blood pressure: SBP; diastolic blood pressure (DBP); CAPS, Caerphilly prospective cohort study. 5 Running title: Vitamin D dietary intake and risk of CVD
6 Author names for indexing: Guo, Cockcroft, Elwood, Pickering, Lovegrove and Givens 7 Word count: 3518
8 Figures: 0 9 Tables: 6
10 OSM submitted: 1
39 Abstract
Background: Prospective data on the associations between vitamin D dietary intake and risk of cardiovascular disease (CVD) and all-cause mortality are limited and inconclusive.
Objectives: To comprehensively investigate the associations between vitamin D dietary intake and CVD risk and all-cause mortality.
Methods: Vitamin D dietary intake was assessed in 452 healthy men who were free from CVD and type 2 diabetes at baseline (1979-1983 years) in the Caerphilly Prospective Cohort Study (CAPS). The associations of vitamin D dietary intake and CVD risk markers were examined cross-sectionally at baseline and longitudinally at the 5 year, 10 year and over 20 year follow-up examinations. Also, the predictive value of vitamin D dietary intake for cardiovascular events and all-cause mortality at 20 years was examined.
Results: After 20 years follow-up, 72 stroke cases, 142 myocardial infarctions (MI), 43 heart failures and 281 cases of all-cause mortality were identified. There was no significant association between vitamin D dietary intake and stroke, MI, heart failure or all-cause mortality. However, higher vitamin D dietary intake was associated with a decreased concentration of plasma triacylglycerol at baseline and 5-years examination. In addition, a modest positive association was found between vitamin D dietary intake and diastolic blood pressure (DBP) after 20-years follow-up.
Conclusions: The results of the current study suggest that a higher vitamin D dietary intake is associated with a lower plasma triacylglycerol level and a higher DBP. Further research is needed to confirm these findings.
Key words: vitamin D, cardiovascular disease, all-cause mortality, Caerphilly Prospective Study, blood pressure, triacylglycerol
40 Introduction
Cardiovascular disease (CVD) is one of the main causes of morbidity and mortality in the world. There is mounting evidence indicating an association between vitamin D deficiency and CVD (1-4). Recently, the UK Scientific Advisory Committee on Nutrition (SACN) (5) reported that in the UK 22-24% of individuals of 19-64 years, and 17-24% of those ≥65 years and above were vitamin D deficient (plasma 25(OH) D3 <25 nmol/L). Humans obtain vitamin D generally from synthesis in the skin due to sunlight ultraviolet radiation and/or foods. However, a number of relatively recent lifestyle changes (e.g. increased working indoors, sunscreen use), personal characteristics (ageing, skin pigmentation) and geographic reasons (latitude), limit the ability to synthesise adequate vitamin D from sunlight (6). As a result vitamin D intake from foods has become more important than previously. This has led SACN to recommend a daily intake of 10 g/day of vitamin D in all adults within the UK (5).
The association between vitamin D deficiency and increased risk of CVD (1-4) and all- cause mortality (7-9) has been investigated, but few prospective cohort studies have analysed the relationship between dietary vitamin D intake and CVD risk and all-cause mortality. In a 10-year cohort of 361 men and 394 women (10), dietary vitamin D intake was shown to have a protective association for stroke, but not myocardial infraction (MI). Another women’s cohort study (11) reported no association between vitamin D dietary intake and all-cause mortality. As the evidence on the association of vitamin D dietary intake and CVD risk or all- cause mortality from prospective cohort studies is limited, we therefore investigated the associations between dietary vitamin D intake and CVD events, CVD risk markers and all- causer mortality using the Caerphilly Prospective Cohort Study (CAPS) which has over 20 years of follow-up.
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Study population
CAPS was initially set up in 1979-1983 to investigate the CVD risk factors based on 2512 men (45-59 years), representing 89% of the subjects living in Caerphilly and the adjacent area (12), which were followed up at 5-year intervals. At Phase 2 (1984-1988), 561 men were lost from Phase 1 (1979-1983) and an additional 447 men were recruited to follow-up. In Phase 1, a representative 30% subsample of subjects (665 men) was randomly selected at baseline to complete a 7-day weighed dietary intake record (13). Food items were coded according to McCance and Widdowson (14). These men were given weighing scales with instructions on how to complete the weighed dietary intake for seven consecutive days. From these records the dietary vitamin D intake was estimated based on food composition data given by McCance and Widdowson (14), additionally, several manufacturers were contacted to obtain more information on new foodstuffs containing mixtures of ingredients (13,15). In order to ensure consistency of the subject group throughout the study, the 134 men from the weighed intake sub-group who dropped out after Phase 1 were excluded from this analysis. In addition, 17 subjects who previously had a heart attack and subjects (n=62) with missing confounding factor data were excluded. Therefore, a total of 452 subjects were available for the current analysis.
Cardiovascular disease events and all-cause mortality
Identification of stroke and vascular disease events was described elsewhere (16, 17). In brief, incidents of all-cause mortality were censored by central Registry NHS in the UK. Identification of fatal and non-fatal vascular disease events (ICD 121-5, 10th revision) including MI, heart failure and stroke (IC 163-4) were according to established criteria (16, 17). Fasting blood samples were taken at baseline and every five years to measure a wide range of CVD risk markers (12). At baseline (Phase 1), at 5-years (Phase 2) and at 10-years
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(Phase 3) examinations, plasma glucose, total-cholesterol and triacylglycerol were measured together with systolic blood pressure (SBP) and diastolic blood pressure (DBP). Insulin and HDL-cholesterol were only measured in Phase 1 and 2. In Phase 5, the haemodynamic variables of SBP, DBP, aortic pulse wave velocity (aPWV), augmentation index (AIx) and mean arterial pressure were measured, the details are described elsewhere (18,19). Pulse pressure was calculated by subtracting DBP from SBP. The Friedewald formula (20) was used to calculate LDL-cholesterol.
Statistics
Data were analysed using STATA (version 13.0; STATA Corporation, 2014). The subjects were divided into four groups according to dietary vitamin D intake. For the analysis of baseline, 5-years and 10-years examinations, logistic regression and general linear regression statistic models were used to investigate the relationships of vitamin D intake with categorical and continuous variables of CVD risk markers, respectively. In addition, logistic regression analyses were used to estimate the odds ratio of stroke, MI, heart failure and all-cause mortality for the longitudinal analysis. The multivariate-adjusted model for all of the analyses first included confounding factors of age (years); body mass index (BMI, kg/m2); social class (manual worker; non-manual worker), smoking (current smoker, never-smoked, ex-smoker), leisure activity (with heavy work or exercise in leisure time, without heavy work or exercise in leisure time), alcohol (as ethanol, ml/week) and food energy intake (MJ/day). In addition, as vitamin D is closely functionally related with calcium, the second multivariate-adjusted model was further adjusted with calcium dietary intake. Results were considered statistically significant at P=0.05 or less.
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The characteristics of the 452 subjects at baseline are shown in Table 1. The average vitamin D intake was 21.0 (SD=19.3) µg per week. Subjects in the lowest quartiles of vitamin D intake were significantly more likely to be smokers (P=0.001) and had higher food energy intake (P<0.001). After controlling for total energy intake from foods, those with the highest vitamin D intake per week tended to have a higher intake of fat (P=0.002), cereal fibre (P<0.001), vegetable fibre (P<0.001), and calcium (P<0.001). There were no associations between dietary vitamin D intake and age, BMI, social class, leisure activity, alcohol consumption, protein intake and carbohydrate intake.
Associations of vitamin D intake with different CVD risk markers were investigated at baseline as a cross-sectional analysis (Phase 1). There was a significant positive association between vitamin D intake and HDL-cholesterol (adjusted model 2 P=0.002; adjusted model 3
P=0.003) (Table 2), with subjects consuming highest vitamin D intake (≥27.3 µg/week)
having 0.13 mmol/L higher HDL-cholesterol levels compared with subjects consuming the lowest vitamin D intake (0.1-9.9 µg/week). In addition, negative associations were observed between vitamin D intake and total/HDL-cholesterol ratio (adjusted model 2 P=0.005; adjusted model 3 P=0.008) and triacylglycerol concentrations (adjusted model 2 P=0.003; adjusted model 3 P=0.013) with the subjects consuming ≥ 27.3 µg/week vitamin D having 0.7 mmol/L lower total/HDL-cholesterol ratio and 0.5 mmol/L lower plasma triacylglycerol compared with subjects consuming the lowest vitamin D intake (0.1-9.9 µg/week). In addition, a positive association was found between vitamin D intake and pulse pressure (adjusted model 2 P=0.026; adjusted model 3 P=0.040).
In the longitudinal analyses of vitamin D intake and CVD risk markers at the 5-year examination (Phase 2), higher vitamin D intake was significantly negatively associated with plasma triacylglycerol concentrations (adjusted model 2 P=0.003; adjusted model 3 P=0.010) (Table 3). The highest vitamin D intake group had 0.48 mmol/L lower plasma triacylglycerol
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than the lowest vitamin D intake group. There were no significant associations between vitamin D intake and other CVD risk markers at the 5-year examination. In the longitudinal analyses at the 10-year examination (Phase 3), only a modest negative association (P=0.056) was found between higher vitamin D intake and plasma triacylglycerol in the un-adjusted model but not in the multivariable adjusted models (Table 4).
After over 20-years follow-up (Phase 5), a tendency for a lower pulse pressure was seen in those with the highest vitamin D intake, but this did not reach significance (Table 5). In the analysis of the associations of SBP and DBP with vitamin D intake, DBP showed a positive correlations with vitamin D intake in the multivariate adjusted models (P=0.041 model 2,
P=0.029 model 3), but no significant associations were found between vitamin D intake and
SBP.
There were no significant associations between dietary vitamin D intake and other CVD risk markers, i.e. fasting glucose/insulin (Supplemental material), mean arterial pressure, pulse wave velocity and augmentation index (Table 5). Also there were no significant associations of vitamin D dietary intake and cardiovascular events (stroke, MI, heart failure) or all-cause mortality after over the 20-years follow-up (Table 6).
Discussion
In this UK prospective cohort study of middle aged men with over 20 years follow-up, we found higher dietary vitamin D intake was associated with lower plasma triacylglycerol concentrations at baseline and the 5-year examination, but not 10-year examinations. In addition, baseline cross-sectional analysis indicated significant positive associations between vitamin D intake and HDL-cholesterol and pulse pressure, with a negative association between vitamin D intake and total/HDL-cholesterol ratio. After over 20 years follow up, a modest positive association was found between vitamin D dietary intake and DBP. In
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contrast, no associations were found between vitamin D and other metabolite markers or disease outcomes of stroke, MI, heart failure and all-cause mortality.
To our knowledge, this is the first prospective study to investigate the associations between dietary vitamin D intake and blood lipid profiles in a generally healthy population using both cross-sectional and longitudinal analyses. The negative association between dietary vitamin D intake and plasma triacylglycerol at baseline and 5-years examination agrees with the results of a 6-month randomized controlled trial (21) in post-menopausal women with type 2 diabetes, which showed that a daily 100 µg dose of vitamin D3 significantly decreased the concentration of serum triacylglycerol (by 1.9 mmol/L, P=0.021). However, it is not clear why the negative association between vitamin D dietary intake and plasma triacylglycerol was found at the 5-year, but not the 10-year of the longitudinal examination. One possible reason may due to dietary change during the follow-up. One study (22) showed that there has been a trend towards a lower fat diet in UK since the 1980s. As vitamin D is fat soluble vitamin (5), it is likely that vitamin D intake has also declined and indeed the current study showed dietary vitamin D intake to be positively associated with fat intake. So the lack of association between dietary vitamin D intake and 10-year triacylglycerol examination may due to dietary vitamin D intake having declined during the follow up. In addition, our study is the first to show a significant positive cross-sectional association between vitamin D intake and pulse pressure, but no association was seen in the longitudinal analysis. In the analysis of the association between vitamin D and SBP or DPB, the only significant finding was a positive association between vitamin D intake and DBP after the 20-year follow-up and which needs confirmation in further studies.
There are very few studies that have reported associations between dietary vitamin D intake and CVD risk or all-cause mortality. Our null finding of dietary vitamin D agree with an earlier prospective study of the Iowa Women’s Healthy Study (WHS) in 1999 (11), which
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also found no association between dietary vitamin D intake and ischaemic heart disease mortality over an 8-year follow-up period. However, vitamin D dietary intake (4.30±3.3 µg/day) was reported in another 10 year follow-up prospective study of 361 men and 394 women (10) and suggested a protective role of dietary vitamin D intake on stroke but not MI. The different conclusions of the above studies may be due to the different characteristics of the study participants. For example, the mean initial age of the subjects in the CAPS (mean age of 51.7 years) and WHS (mean age of 53.8 years) were similar, but higher (age range of 65-99 years) in the investigation of Marniemi et al. (10). Furthermore, our study agrees with a systematic review of 56 randomised controlled trails, which did not find a significant association between vitamin D supplementation and total mortality risk (23).
The recent report of the UK Scientific Advisory Committee on Nutrition (5) recommended a daily Reference Nutrient Intake (RNI) of 10 µg vitamin D for the general population aged 4 years and above, including pregnant and lactating women. In CAPS, only 11 out of 452 subjects achieved the current RNI dose. Therefore, the effect of dietary vitamin D may have been minimised by the low dietary vitamin D intake. However, a few recent studies have used higher doses of vitamin D in their intervention trials (24-26), which also showed no associations of vitamin D supplementation with markers of CVD risk.
The strength of the CAPS is the long (over 20 years) follow-up period. This novel study presents both cross-sectional and longitudinal relationships between dietary vitamin D intake and CVD events. The longitudinal analysis was conducted at 5, 10 and over 20 years which provide the opportunity to test the consistency of the influence of vitamin D intake on CVD events. There are however several limitations of this study. First, vitamin D dietary intake was only assessed at baseline, and was not repeated in the other phases to assess the extent of any diet change. Second, the results apply to men only, which may not represent the effect in women. Finally, unknown residual confounding factors may have influenced the outcomes
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seen. In particular, the vitamin D status of the subjects was not measured initially and during the follow-up of CAPS and there were no assessments of sunshine exposure. In addition, because the small cohort size of the current study may not be representative all of UK men, further prospective studies with large subject numbers can provide more evidence on effect of the vitamin D dietary intake on CVD risk and/or all-cause mortality.
Conclusion
The current investigation from CAPS prospective cohort study provides further evidence for the potential benefits of vitamin D intake on circulating triacylglycerol concentrations at baseline and also the 5-years examination. After over 20 years follow-up, higher vitamin D dietary intake is associated with a higher DBP. Future studies are needed to verify the current findings, especially randomised controlled intervention trials on the effect of dietary vitamin D intake on CVD risk markers in subjects of low vitamin D status.
Acknowledgements
The authors’ responsibilities were as follows: JG, JAL and DIG designed the research; JG conducted the research; JG analysed the data with guidance from JEP; JG, DIG and JAL wrote the paper; PCE and JRC contributed expertise on epidemiology and CVD respectively. DIG and JAL had primary responsibility for the final content of the manuscript. All authors read and approved the final manuscript. None of the authors had a conflict of interest. We thank Professor Yoav Ben-Shlomo, School of Social and Community Medicine, University of Bristol for managing the release of data from the CAPS.
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