- Email: [email protected]
Vitamin D and Cardiometabolic Risks
CHAPTER
25
Vitamin D and Cardiometabolic Risks F.R. Pérez-López*, A.M. Fernández-Alonso†, P. Chedraui‡, T. Simoncini}
Universidad de Zaragoza, Zaragoza, Spain Hospital Torreca´rdenas, Almeria, Spain Universidad Cato´lica de Santiago de Guayaquil, Guayaquil, Ecuador } University of Pisa, Pisa, Italy †
‡
ABBREVIATIONS 1,25(OH)2D 1,25-dihydroxy-vitamin D or calcitriol 25(OH)D 25-hydroxyvitamin D or calcidiol BMI Body mass index CVD Cardiovascular disease HDL-C High-density lipoprotein cholesterol HOMA-IR Homeostasis model assessment of insulin resistance IR Insulin resistance LDL-C Low-density lipoprotein cholesterol NHANES-III Third US National Health and Nutrition Examination Survey T2DM Type 2 diabetes mellitus
1. INTRODUCTION Vitamin D shares properties of both vitamins and hormones. It is acquired both by successive synthesis at the skin, liver, and kidneys or digestive absorption in the upper part of the small intestine through the actions of bile salts. Vitamin D from both sources is stored in the adipose tissue. Although its regulatory actions on calcium and bone metabolism are the most well-known functions, other pleiotropic effects are not less important, including actions over the cardiovascular system. Vitamin D receptors are present in endothelial cells, vascular smooth muscle cells, and cardiomyocytes. The vitamin is capable of affecting inflammation, proliferation, and differentiation. In addition, nongenomic actions are also operative in many cell types (Pe´rez-Lo´pez, 2009; Pe´rez-Lo´pez et al., 2011). Basic, experimental, and clinical evidence support the association between vitamin D and cardiovascular risk factors. Thus, hypovitaminosis D is linked to alterations in glucose and lipoprotein metabolism, diabetes, hypertension, and obesity. Endogenous vitamin D status is generally determined by plasma levels of 25-hydroxyvitamin D [25(OH)D] or calcidiol, although the bioactive compound is the one-alpha hydroxylated derivative with a shorter half life: 1,25-dihydroxy-vitamin D [1,25(OH)2D] or calcitriol. Serum Bioactive Food as Dietary Interventions for Cardiovascular Disease http://dx.doi.org/10.1016/B978-0-12-396485-4.00023-2
#
2013 Elsevier Inc. All rights reserved.
385
386
F.R. Pérez-López et al.
25(OH)D levels are expressed as ng ml1 or nmol l1, being the equivalence of 1 ng ml1 ¼ 2.5 nmol l1. This chapter reviews relevant aspects concerning the effects of low plasma vitamin D on the metabolic syndrome (METS) and cardiovascular-related risks.
2. THE METABOLIC SYNDROME METS is a cluster of metabolic alterations including abdominal adiposity, hypertension, insulin resistance (IR), dyslipidemia, proinflammatory status, and increased thrombosis risk. The syndrome is linked to type 2 diabetes mellitus (T2DM), cardiovascular disease (CVD), and overall mortality. It is suspected that visceral fat secretes several inflammatory adipokines that precipitate both IR and an inflammatory status (Elks and Francis, 2010). In diabetic and nondiabetic individuals low plasma vitamin D levels have been linked to inflammatory endothelial dysfunction (Yiu et al., 2011). Despite this, the etiology of the METS is complex and includes genetic, metabolic, and lifestyle factors. The third US National Health and Nutrition Examination Survey (NHANES-III) found that mean serum 25(OH)D levels were significantly lower among individuals with the METS as compared with those without the syndrome (67.1 vs. 75.9 nmol l1; Ford et al., 2005). Individuals with 25(OH)D levels below 20 ng ml1 had a higher prevalence of the METS components (Chiu et al., 2004). In general, it seems there is an inverse correlation between serum 25(OH)D levels and the METS prevalence, suggesting that the vitamin has some degree of protective effect (Kayaniyil et al., 2011). An association between serum 25(OH)D levels and components of the METS has been reported in nonobese young individuals. Serum 25(OH)D is inversely correlated with body mass index (BMI), systolic blood pressure, waist circumference, fasting glucose and insulin levels, and the homeostasis model assessment of insulin resistance (HOMAIR), whereas positively correlated with adiponectin and high-density lipoprotein cholesterol (HDL-C) levels (Gannage´-Yared et al., 2009). These observations seem in some way the initial status of what could be the outcome in older individuals. Despite this, further studies are required.
3. IR, DIABETES, AND VITAMIN D Epidemiological evidence supports the fact that hypovitaminosis D increases IR, with associations observed between serum 25(OH)D levels and glycemia, insulin secretion, and T2DM prevalence. The prevalence of low serum 25(OH)D levels (37.5 nmol l1) is 34% among adults with T2DM as compared to nondiabetics. In addition, diabetic patients with low vitamin D levels have increased thickening of the common carotid medial intima (indirect marker of atherosclerosis) as compared to diabetics with normal vitamin D levels (Targher et al., 2006).
Vitamin D and Cardiometabolic Risks
The value of serum 25(OH)D levels in predicting future glycemic status and IR has been studied in nondiabetic subjects 40–69 years followed up for 10 years. Baseline 25 (OH)D levels were inversely associated to a 10-year risk for hyperglycemia, IR, and METS (Forouhi et al., 2008). Associations between plasma 25(OH)D levels and indirect markers of IR have been studied in nondiabetic subjects of the Framingham Offspring Study. After adjusting for confounding factors, plasma 25(OH)D levels were inversely associated to HOMA-IR and fasting glucose and insulin plasma levels. When subjects were stratified by 25(OH)D tertiles, those in the highest tertile group had lower glucose (1.6%), insulin (9.8%), and HOMA-IR (12.7%) levels. In addition, plasma 25(OH)D levels were associated to the insulin sensitivity index, adiponectin, and HDL-C and inversely to plasma triacylglycerol levels. However, these associations were no longer significant after further adjustment for BMI, waist circumference, and current smoking status. No association has been observed between serum 25(OH)D and 2-h postoral glucose tolerance test values (Liu et al., 2009). The influence of metabolic and anthropometric variables and lifestyle over 25(OH)D levels have been assessed in native Americans without type 1 diabetes or T2DM from Cree communities (South Canada). Multiple regression analysis determined that serum 25(OH)D (per 10 nmol l1 increment) was inversely associated to HOMA-IR and b-cell function. However, when adjustments for age, sex, physical activity, education, alcohol consumption, and smoking were carried out, associations disappeared (Del Gobbo et al., 2011). Further studies are needed in other populations to better delineate the effect of cofactors influencing the relationship between pancreatic function and vitamin D metabolism. It has been suggested that vitamin D and calcium supplements may be important in the prevention of T2DM. A recent meta-analysis of heterogeneous studies reported that three of six analyses showed a lower diabetes risk in the highest compared to the lowest vitamin D status groups, and eight trials found no effect of vitamin D supplementation over glucose levels or incident diabetes (Pittas et al., 2010). The oral administration of a 100 000 IU of cholecalciferol (2 weeks apart) in nondiabetic subjects with low serum 25(OH)D levels (50 nmol l1) increased vitamin D levels from a mean of 39.9 to 90.3 4.3 nmol l1, with no changes observed in mean blood glucose or insulin concentrations (including insulin sensitivity; Tai et al., 2008).
4. OVERWEIGHT, OBESITY, AND VITAMIN D Although abdominal adiposity mass has a pivotal role in the development of the METS, adipose tissue dysfunction may be more relevant to IR and other metabolic changes (associated to METS and cardiovascular risk) than to the amount of fat mass per se (Chandalia and Abate, 2007). Vitamin D is a group of fat soluble compounds with a tropism for the adipose tissue. Functions within this tissue are to date unknown.
387
388
F.R. Pérez-López et al.
Administration of pharmacological doses of vitamin D increases the fraction of circulating free vitamin D, and its metabolites accumulate in adipose tissue and muscle (Vieth, 1999). After prolonged sunlight exposure blood vitamin D levels increase and may saturate the capacity of its binding protein. Consequently, excessive free vitamin D is stored in the adipose tissue. In relation to this, many studies have reported that low serum 25(OH)D levels are more prevalent among overweight and obese subjects. Therefore, adipose tissue may serve as a buffer when vitamin D acquisition is high and produce its slow release during fasting conditions. Increased body weight is linked to hypertension and lipid abnormalities, and cardiovascular risk independent of hyperinsulinemia. Low plasma vitamin D levels have been reported in obese patients. However, it is unlikely that the inverse associations found between BMI and serum 25(OH)D and 1,25(OH)D levels contribute to obesity development (Parikh et al., 2004). Reports have linked low 25(OH)D levels and obesity (BMI or waist circumference defined). It has been estimated that vitamin D decreases 0.74 and 0.29 nmol l1 for every increase in 1 kg m2 for BMI and 1 cm increase in waist, respectively (McGill et al., 2008). Fat excess makes vitamin D less available for body use. Many obese subjects have disturbances in body imaging and low self esteem and therefore minimize sunlight exposure. However, sun exposure habits do not differ according to adiposity, and do not explain low 25(OH)D with increasing body fat mass. In addition, body fat composition and vitamin D relationship is influenced by skin characteristics. Metabolic status in the presence of excess body fat mass is quite complex and influenced by different hormones. The relevance of vitamin D status in relation to cardiovascular risk remains to be determined. Nevertheless, it seems reasonable that obese individuals receive vitamin D supplements to prevent the long-term consequences of hypovitaminosis.
5. LIPOPROTEINS AND VITAMIN D Studies of healthy men and women from several ethnic groups have found that low vitamin D status adversely affects total cholesterol and low-density lipoprotein cholesterol (LDL-C) concentrations (Pe´rez-Lo´pez, 2009; Pe´rez-Lo´pez et al., 2011). In mid-aged Finish men who are not receiving antidiabetic treatment, low 1,25(OH)2D levels were associated to low HDL-C, whereas low serum 25(OH)D levels correlated to high total cholesterol, LDL-C and triglyceride levels (Karhapa¨a¨ et al., 2010). This lipid profiling increases cardiovascular risk. The Troms University cohort of nearly 8000 subjects followed for more than 14 years reported an association between 25(OH)D and lipoproteins which may explain the link between vitamin D status and cardiovascular mortality. Serum total cholesterol, HDL-C, and LDL-C levels significantly increased and LDL-C/ HDL-C ratio and triacylglycerol levels decreased with increasing 25(OH)D levels expressed as quartiles (Jorde et al., 2010).
Vitamin D and Cardiometabolic Risks
6. HYPERTENSION There is experimental, epidemiological, and clinical evidence linking low vitamin D status and hypertension. Impaired vascular health in correlation with lower vitamin D levels would contribute to hypertension and CVD risk. The results from the NHANES-III, carried out during 1988–94, reported an inverse association between serum 25(OH)D and blood pressure levels that was evident even after adjusting for several cofactors such as age, gender, ethnicity, and physical activity. In addition, when subjects were classified into 25(OH)D quintiles, those in highest quintile as compared to those in the lowest displayed lower mean systolic and diastolic blood pressures (3.0 and 1.6 mmHg, respectively) (Scragg et al., 2007). In a more recent analysis of the same cohort, overall serum 25(OH)D levels were lower in 2000–04 than in 1988–94 which were justified by measurement methods, but also due to changes in relation to BMI, milk intake, sun protection that contribute to a real descent in vitamin D status (Looker et al., 2008). The association between blood pressure and vitamin D status is contradictory in general due to methodological gaps. Other explanations include that low vitamin D levels probably increase blood pressure via inhibiting the renin–angiotensin system. In this regard, low vitamin D should be below a certain threshold that produces renin increases. Therefore, it would be unlikely that vitamin D supplementation produce any blood pressure decrease in normotensive subjects because renin levels are normal.
7. CVD AND VITAMIN D The large cohort of the Intermountain Heart Collaborative Study Group reported a relationship between vitamin D levels and cardiovascular risk factors, disease status and incidental events. Low vitamin D status was associated with significant increases in the prevalence of diabetes, hypertension, hyperlipidemia, and peripheral vascular disease. In addition, vitamin D was also associated to coronary artery disease, myocardial infarction, heart failure, and stroke (Anderson et al., 2010). Serum 25(OH)D status is an independent risk factor for CVD. In the NHANES-III cohort CVD prevalence was higher in individuals with 25(OH)D levels below 20 ng ml1 as compared to those with higher levels (Kendrick et al., 2009). After adjusting for a long list of cofactors related to CVD, a strong and independent association emerged between 25(OH)D and CVD prevalence. After a 14-year follow up another recent NHANES-III report found that among Caucasians but not blacks fatal stroke was linked to low vitamin D levels (Michos, 2010). Serum 25(OH)D levels were measured in acute myocardial infarction patients enrolled in a 20-hospital US prospective registry. Serum 25(OH)D deficiency (20 ng ml1) was more common among non-Caucasian patients, and those with lower
389
390
F.R. Pérez-López et al.
social support, no insurance, diabetes, and less physical activity. Thus, vitamin D deficiency is present in almost all acute myocardial infarction patients (Lee et al., 2011). Reports indicate that low serum vitamin D levels may increase mortality risk due to CVD, cancer and other chronic diseases. It has been postulated, although not proven, that high endogenous vitamin D status could increase longevity (Pe´rez-Lo´pez et al., 2011). A meta-analysis reported that vitamin D (300–2000 IU day1; mean dose 528 IU) supplementation for an average of 5 or more years decreased risk for all-cause death by 7% (Autier and Gandini, 2007). The systematic review of prospective studies and randomized trials regarding calcium and/or vitamin D supplementation and subsequent cardiovascular events showed that vitamin D supplementation produces a nonsignificant reduction in CVD risk, whereas calcium or the vitamin D plus calcium supplementation had no effect (Wang et al., 2010).
8. FINAL REMARKS A significant proportion of the world population has low serum vitamin D levels which may negatively affect components of the METS and CVD associated conditions. The molecular mechanisms of these associations remain incompletely understood. Low sun exposure, use of sunscreens, changes in lifestyle, dietary habits, obesity, and other environmental factors contribute to hypovitaminosis D. The controversial puzzling results are due to complex metabolic mechanisms acting on the cardiocirculatory tree. Although vitamin D is not the health panacea, optimal vitamin D status should be a major task in order to improve health in the present generation. A traditional lifestyle with a vitamin D enriched natural diet, exposure to sunlight in a responsible manner and regular outdoor activities should be highly recommended. ‘Normal’ vitamin D levels required for optimal cell functioning are still unknown. In addition, causes of death may be confounded or poorly specified and hence result in bias. Nevertheless, low 25(OH)D levels do seem to be a marker of poor health. The ongoing Vitamin D and Omega-3 Trial (VITAL) will provide answers to many questions and hopefully confirm the benefits of vitamin D.
GLOSSARY Metabolic syndrome A cluster of metabolic risk factors including abdominal obesity, hypertension, insulin resistance, dyslipidemia, proinflammatory status, and increased thrombosis risk. Vitamin D A group of fat soluble secosteroids that exerts actions through both specific receptor and nongenomic mechanisms. Vitamin D receptor Cell structure that specifically binds vitamin D to initiate molecular changes.
Vitamin D and Cardiometabolic Risks
REFERENCES Anderson, J.L., May, H.T., Horne, B.D., et al., 2010. Intermountain Heart Collaborative (IHC) Study Group. Relation of vitamin D deficiency to cardiovascular risk factors, disease status, and incident events in a general healthcare population. The American Journal of Cardiology 106, 963–968. Autier, P., Gandini, S., 2007. Vitamin D supplementation and total mortality: a meta-analysis of randomized controlled trials. Archives of Internal Medicine 167, 1730–1737. Chandalia, M., Abate, N., 2007. Metabolic complications of obesity: inflated or inflamed? Journal of Diabetes and its Complications 21, 128–136. Chiu, K.C., Chu, A., Go, V.L., Saad, M.F., 2004. Hypovitaminosis D is associated with insulin resistance and beta cell dysfunction. American Journal of Clinical Nutrition 79, 820–825. Del Gobbo, L.C., Song, Y., Dannenbaum, D.A., Dewailly, E., Egeland, G.M., 2011. Serum 25-hydroxyvitamin D is not associated with insulin resistance or beta cell function in Canadian Cree. Journal of Nutrition 141, 290–295. Elks, C.M., Francis, J., 2010. Central adiposity, systemic inflammation, and the metabolic syndrome. Current Hypertension Reports 12, 99–104. Ford, E.S., Ajani, U.A., McGuire, L.C., Liu, S., 2005. Concentrations of serum vitamin D and the metabolic syndrome among U.S. adults. Diabetes Care 28, 1228–1230. Forouhi, N.G., Luan, J., Cooper, A., Boucher, B.J., Wareham, N.J., 2008. Baseline serum 25-hydroxy vitamin D is predictive of future glycemic status and insulin resistance: the Medical Research Council Ely Prospective Study 1990–2000. Diabetes 57, 2619–2625. Gannage´-Yared, M.H., Chedid, R., Khalife, S., et al., 2009. Vitamin D in relation to metabolic risk factors, insulin sensitivity and adiponectin in a young Middle-Eastern population. European Journal of Endocrinology 160, 965–971. Jorde, R., Figenschau, Y., Hutchinson, M., Emaus, N., Grimnes, G., 2010. High serum 25-hydroxyvitamin D concentrations are associated with a favorable serum lipid profile. European Journal of Clinical Nutrition 64, 1457–1464. Karhapa¨a¨, P., Pihlajama¨ki, J., Po¨rsti, I., et al., 2010. Diverse associations of 25-hydroxyvitamin D and 1,25-dihydroxy-vitamin D with dyslipidaemias. Journal of Internal Medicine 268, 604–610. Kayaniyil, S., Vieth, R., Harris, S.B., et al., 2011. Association of 25(OH)D and PTH with metabolic syndrome and its traditional and nontraditional components. Journal of Clinical Endocrinology and Metabolism 96, 168–175. Kendrick, J., Targher, G., Smits, G., Chonchol, M., 2009. 25-Hydroxyvitamin D deficiency is independently associated with cardiovascular disease in the Third National Health and Nutrition Examination Survey. Atherosclerosis 205, 255–260. Lee, J.H., Gadi, R., Spertus, J.A., Tang, F., O’ Keefe, J.H., 2011. Prevalence of vitamin D deficiency in patients with acute myocardial infarction. The American Journal of Cardiology 107 (11), 1636–1638. Liu, E., Meigs, J.B., Pittas, A.G., et al., 2009. Plasma 25-hydroxyvitamin D is associated with markers of the insulin resistant phenotype in nondiabetic adults. Journal of Nutrition 139, 329–334. Looker, A.C., Pfeiffer, C.M., Lacher, D.A., et al., 2008. Serum 25-hydroxyvitamin D status of the US population: 1988–1994 compared with 2000–2004. American Journal of Clinical Nutrition 88, 1519–1527. McGill, A.T., Stewart, J.M., Lithander, F.E., Strik, C.M., Poppitt, S.D., 2008. Relationships of low serum vitamin D3 with anthropometry and markers of the metabolic syndrome and diabetes in overweight and obesity. Nutrition Journal 7, 4. Michos, E., 2010. Vitamin-D deficiency linked to fatal stroke in whites but not blacks. Risk of fatal stroke associated with vitamin-D deficiency (25[OH]D <15 ng/mL) in white vs black participants. Available from: http://www.theheart.org/article/1149285.do (accessed 30 March 2011). Parikh, S.J., Edelman, M., Uwaifo, G.I., et al., 2004. The relationship between obesity and serum 1,25-dihydroxy vitamin D concentrations in healthy adults. Journal of Clinical Endocrinology and Metabolism 89, 1196–1199. Pe´rez-Lo´pez, F.R., 2009. Vitamin D metabolism and cardiovascular risk factors in postmenopausal women. Maturitas 62, 248–262.
391
392
F.R. Pérez-López et al.
Pe´rez-Lo´pez, F.R., Chedraui, P., Ferna´ndez-Alonso, A.M., 2011. Vitamin D and aging: beyond calcium and bone metabolism. Maturitas 69, 27–36. Pittas, A.G., Chung, M., Trikalinos, T., et al., 2010. Systematic review: vitamin D and cardiometabolic outcomes. Annals of Internal Medicine 152, 307–314. Scragg, R., Sowers, M., Bell, C., 2007. Serum 25-hydroxyvitamin D, ethnicity, and blood pressure in the Third National Health and Nutrition Examination Survey. American Journal of Hypertension 20, 713–719. Tai, K., Need, A.G., Horowitz, M., Chapman, I.M., 2008. Glucose tolerance and vitamin D: effects of treating vitamin D deficiency. Nutrition 24, 950–956. Targher, G., Bertolini, L., Padovani, R., et al., 2006. Serum 25-hydroxyvitamin D3 concentrations and carotid artery intima-media thickness among type 2 diabetic patients. Clinical Endocrinology 65, 593–597. Vieth, R., 1999. Vitamin D supplementation, 25-hydroxyvitamin D concentrations, and safety. American Journal of Clinical Nutrition 69, 842–856. Wang, L., Manson, J.E., Song, Y., Sesso, H.D., 2010. Systematic review: vitamin D and calcium supplementation in prevention of cardiovascular events. Annals of Internal Medicine 152, 315–323. Yiu, Y.F., Chan, Y.H., Yiu, K.H., et al., 2011. Vitamin D deficiency is associated with depletion of circulating endothelial progenitor cells and endothelial dysfunction in patients with type 2 diabetes. Journal of Clinical Endocrinology and Metabolism 8 (1), 47–52.
FURTHER READING Bischoff-Ferrari, H.A., Shao, A., Dawson-Hughes, B., 2010. Benefit-risk assessment of vitamin D supplementation. Osteoporosis International 21, 1121–1132.http://www.ncbi.nlm.nih.gov/pmc/articles/ PMC3062161/pdf/nihms-280261.pdf. Grant, W.B., 2009. In defense of the sun: an estimate of changes in mortality rates in the United States if mean serum 25-hydroxyvitamin D levels were raised to 45 ng/mL by solar ultraviolet-B irradiance. Dermatoendocrinol 1, 207–214. Kulie, T., Groff, A., Redmer, J., Hounshell, J., Schrager, S., 2009. Vitamin D: an evidence-based review. Journal of the American Board of Family Medicine 22, 698–706.http://www.jabfm.org/cgi/ pmidlookup?view¼long&pmid¼19897699. Manson, J.E., 2010. Vitamin D and the heart: why we need large-scale clinical trials. Cleveland Clinic Journal of Medicine 77, 903–910.http://www.ccjm.org/content/77/12/903.full.pdfþhtml. Ross, A.C., Manson, J.E., Abrams, S.A., et al., 2011. The 2011 report on dietary reference intakes for calcium and vitamin D from the Institute of Medicine: what clinicians need to know. Journal of Clinical Endocrinology and Metabolism 96, 53–58.http://www.ncbi.nlm.nih.gov/pmc/articles/ PMC3046611/?tool¼pubmed.
Relevant Websites http://www.iom.edu/Reports/2010/Dietary-Reference-Intakes-for-Calcium-and-Vitamin-D.aspx – Institute of Medicine. Dietary reference intakes for calcium and vitamin D. http://ods.od.nih.gov/factsheets/vitamind/ – National Institutes of health. Office of Dietary Supplements. Vitamin D. http://www.naturaldatabase.com – Natural Medicines. Comprehensive database. Vitamin D. http://www.vitamindsociety.org/ – The Vitamin D Society. http://www.vitamindcouncil.org/ – Vitamin D council.
25
Vitamin D and Cardiometabolic Risks F.R. Pérez-López*, A.M. Fernández-Alonso†, P. Chedraui‡, T. Simoncini}
Universidad de Zaragoza, Zaragoza, Spain Hospital Torreca´rdenas, Almeria, Spain Universidad Cato´lica de Santiago de Guayaquil, Guayaquil, Ecuador } University of Pisa, Pisa, Italy †
‡
ABBREVIATIONS 1,25(OH)2D 1,25-dihydroxy-vitamin D or calcitriol 25(OH)D 25-hydroxyvitamin D or calcidiol BMI Body mass index CVD Cardiovascular disease HDL-C High-density lipoprotein cholesterol HOMA-IR Homeostasis model assessment of insulin resistance IR Insulin resistance LDL-C Low-density lipoprotein cholesterol NHANES-III Third US National Health and Nutrition Examination Survey T2DM Type 2 diabetes mellitus
1. INTRODUCTION Vitamin D shares properties of both vitamins and hormones. It is acquired both by successive synthesis at the skin, liver, and kidneys or digestive absorption in the upper part of the small intestine through the actions of bile salts. Vitamin D from both sources is stored in the adipose tissue. Although its regulatory actions on calcium and bone metabolism are the most well-known functions, other pleiotropic effects are not less important, including actions over the cardiovascular system. Vitamin D receptors are present in endothelial cells, vascular smooth muscle cells, and cardiomyocytes. The vitamin is capable of affecting inflammation, proliferation, and differentiation. In addition, nongenomic actions are also operative in many cell types (Pe´rez-Lo´pez, 2009; Pe´rez-Lo´pez et al., 2011). Basic, experimental, and clinical evidence support the association between vitamin D and cardiovascular risk factors. Thus, hypovitaminosis D is linked to alterations in glucose and lipoprotein metabolism, diabetes, hypertension, and obesity. Endogenous vitamin D status is generally determined by plasma levels of 25-hydroxyvitamin D [25(OH)D] or calcidiol, although the bioactive compound is the one-alpha hydroxylated derivative with a shorter half life: 1,25-dihydroxy-vitamin D [1,25(OH)2D] or calcitriol. Serum Bioactive Food as Dietary Interventions for Cardiovascular Disease http://dx.doi.org/10.1016/B978-0-12-396485-4.00023-2
#
2013 Elsevier Inc. All rights reserved.
385
386
F.R. Pérez-López et al.
25(OH)D levels are expressed as ng ml1 or nmol l1, being the equivalence of 1 ng ml1 ¼ 2.5 nmol l1. This chapter reviews relevant aspects concerning the effects of low plasma vitamin D on the metabolic syndrome (METS) and cardiovascular-related risks.
2. THE METABOLIC SYNDROME METS is a cluster of metabolic alterations including abdominal adiposity, hypertension, insulin resistance (IR), dyslipidemia, proinflammatory status, and increased thrombosis risk. The syndrome is linked to type 2 diabetes mellitus (T2DM), cardiovascular disease (CVD), and overall mortality. It is suspected that visceral fat secretes several inflammatory adipokines that precipitate both IR and an inflammatory status (Elks and Francis, 2010). In diabetic and nondiabetic individuals low plasma vitamin D levels have been linked to inflammatory endothelial dysfunction (Yiu et al., 2011). Despite this, the etiology of the METS is complex and includes genetic, metabolic, and lifestyle factors. The third US National Health and Nutrition Examination Survey (NHANES-III) found that mean serum 25(OH)D levels were significantly lower among individuals with the METS as compared with those without the syndrome (67.1 vs. 75.9 nmol l1; Ford et al., 2005). Individuals with 25(OH)D levels below 20 ng ml1 had a higher prevalence of the METS components (Chiu et al., 2004). In general, it seems there is an inverse correlation between serum 25(OH)D levels and the METS prevalence, suggesting that the vitamin has some degree of protective effect (Kayaniyil et al., 2011). An association between serum 25(OH)D levels and components of the METS has been reported in nonobese young individuals. Serum 25(OH)D is inversely correlated with body mass index (BMI), systolic blood pressure, waist circumference, fasting glucose and insulin levels, and the homeostasis model assessment of insulin resistance (HOMAIR), whereas positively correlated with adiponectin and high-density lipoprotein cholesterol (HDL-C) levels (Gannage´-Yared et al., 2009). These observations seem in some way the initial status of what could be the outcome in older individuals. Despite this, further studies are required.
3. IR, DIABETES, AND VITAMIN D Epidemiological evidence supports the fact that hypovitaminosis D increases IR, with associations observed between serum 25(OH)D levels and glycemia, insulin secretion, and T2DM prevalence. The prevalence of low serum 25(OH)D levels (37.5 nmol l1) is 34% among adults with T2DM as compared to nondiabetics. In addition, diabetic patients with low vitamin D levels have increased thickening of the common carotid medial intima (indirect marker of atherosclerosis) as compared to diabetics with normal vitamin D levels (Targher et al., 2006).
Vitamin D and Cardiometabolic Risks
The value of serum 25(OH)D levels in predicting future glycemic status and IR has been studied in nondiabetic subjects 40–69 years followed up for 10 years. Baseline 25 (OH)D levels were inversely associated to a 10-year risk for hyperglycemia, IR, and METS (Forouhi et al., 2008). Associations between plasma 25(OH)D levels and indirect markers of IR have been studied in nondiabetic subjects of the Framingham Offspring Study. After adjusting for confounding factors, plasma 25(OH)D levels were inversely associated to HOMA-IR and fasting glucose and insulin plasma levels. When subjects were stratified by 25(OH)D tertiles, those in the highest tertile group had lower glucose (1.6%), insulin (9.8%), and HOMA-IR (12.7%) levels. In addition, plasma 25(OH)D levels were associated to the insulin sensitivity index, adiponectin, and HDL-C and inversely to plasma triacylglycerol levels. However, these associations were no longer significant after further adjustment for BMI, waist circumference, and current smoking status. No association has been observed between serum 25(OH)D and 2-h postoral glucose tolerance test values (Liu et al., 2009). The influence of metabolic and anthropometric variables and lifestyle over 25(OH)D levels have been assessed in native Americans without type 1 diabetes or T2DM from Cree communities (South Canada). Multiple regression analysis determined that serum 25(OH)D (per 10 nmol l1 increment) was inversely associated to HOMA-IR and b-cell function. However, when adjustments for age, sex, physical activity, education, alcohol consumption, and smoking were carried out, associations disappeared (Del Gobbo et al., 2011). Further studies are needed in other populations to better delineate the effect of cofactors influencing the relationship between pancreatic function and vitamin D metabolism. It has been suggested that vitamin D and calcium supplements may be important in the prevention of T2DM. A recent meta-analysis of heterogeneous studies reported that three of six analyses showed a lower diabetes risk in the highest compared to the lowest vitamin D status groups, and eight trials found no effect of vitamin D supplementation over glucose levels or incident diabetes (Pittas et al., 2010). The oral administration of a 100 000 IU of cholecalciferol (2 weeks apart) in nondiabetic subjects with low serum 25(OH)D levels (50 nmol l1) increased vitamin D levels from a mean of 39.9 to 90.3 4.3 nmol l1, with no changes observed in mean blood glucose or insulin concentrations (including insulin sensitivity; Tai et al., 2008).
4. OVERWEIGHT, OBESITY, AND VITAMIN D Although abdominal adiposity mass has a pivotal role in the development of the METS, adipose tissue dysfunction may be more relevant to IR and other metabolic changes (associated to METS and cardiovascular risk) than to the amount of fat mass per se (Chandalia and Abate, 2007). Vitamin D is a group of fat soluble compounds with a tropism for the adipose tissue. Functions within this tissue are to date unknown.
387
388
F.R. Pérez-López et al.
Administration of pharmacological doses of vitamin D increases the fraction of circulating free vitamin D, and its metabolites accumulate in adipose tissue and muscle (Vieth, 1999). After prolonged sunlight exposure blood vitamin D levels increase and may saturate the capacity of its binding protein. Consequently, excessive free vitamin D is stored in the adipose tissue. In relation to this, many studies have reported that low serum 25(OH)D levels are more prevalent among overweight and obese subjects. Therefore, adipose tissue may serve as a buffer when vitamin D acquisition is high and produce its slow release during fasting conditions. Increased body weight is linked to hypertension and lipid abnormalities, and cardiovascular risk independent of hyperinsulinemia. Low plasma vitamin D levels have been reported in obese patients. However, it is unlikely that the inverse associations found between BMI and serum 25(OH)D and 1,25(OH)D levels contribute to obesity development (Parikh et al., 2004). Reports have linked low 25(OH)D levels and obesity (BMI or waist circumference defined). It has been estimated that vitamin D decreases 0.74 and 0.29 nmol l1 for every increase in 1 kg m2 for BMI and 1 cm increase in waist, respectively (McGill et al., 2008). Fat excess makes vitamin D less available for body use. Many obese subjects have disturbances in body imaging and low self esteem and therefore minimize sunlight exposure. However, sun exposure habits do not differ according to adiposity, and do not explain low 25(OH)D with increasing body fat mass. In addition, body fat composition and vitamin D relationship is influenced by skin characteristics. Metabolic status in the presence of excess body fat mass is quite complex and influenced by different hormones. The relevance of vitamin D status in relation to cardiovascular risk remains to be determined. Nevertheless, it seems reasonable that obese individuals receive vitamin D supplements to prevent the long-term consequences of hypovitaminosis.
5. LIPOPROTEINS AND VITAMIN D Studies of healthy men and women from several ethnic groups have found that low vitamin D status adversely affects total cholesterol and low-density lipoprotein cholesterol (LDL-C) concentrations (Pe´rez-Lo´pez, 2009; Pe´rez-Lo´pez et al., 2011). In mid-aged Finish men who are not receiving antidiabetic treatment, low 1,25(OH)2D levels were associated to low HDL-C, whereas low serum 25(OH)D levels correlated to high total cholesterol, LDL-C and triglyceride levels (Karhapa¨a¨ et al., 2010). This lipid profiling increases cardiovascular risk. The Troms University cohort of nearly 8000 subjects followed for more than 14 years reported an association between 25(OH)D and lipoproteins which may explain the link between vitamin D status and cardiovascular mortality. Serum total cholesterol, HDL-C, and LDL-C levels significantly increased and LDL-C/ HDL-C ratio and triacylglycerol levels decreased with increasing 25(OH)D levels expressed as quartiles (Jorde et al., 2010).
Vitamin D and Cardiometabolic Risks
6. HYPERTENSION There is experimental, epidemiological, and clinical evidence linking low vitamin D status and hypertension. Impaired vascular health in correlation with lower vitamin D levels would contribute to hypertension and CVD risk. The results from the NHANES-III, carried out during 1988–94, reported an inverse association between serum 25(OH)D and blood pressure levels that was evident even after adjusting for several cofactors such as age, gender, ethnicity, and physical activity. In addition, when subjects were classified into 25(OH)D quintiles, those in highest quintile as compared to those in the lowest displayed lower mean systolic and diastolic blood pressures (3.0 and 1.6 mmHg, respectively) (Scragg et al., 2007). In a more recent analysis of the same cohort, overall serum 25(OH)D levels were lower in 2000–04 than in 1988–94 which were justified by measurement methods, but also due to changes in relation to BMI, milk intake, sun protection that contribute to a real descent in vitamin D status (Looker et al., 2008). The association between blood pressure and vitamin D status is contradictory in general due to methodological gaps. Other explanations include that low vitamin D levels probably increase blood pressure via inhibiting the renin–angiotensin system. In this regard, low vitamin D should be below a certain threshold that produces renin increases. Therefore, it would be unlikely that vitamin D supplementation produce any blood pressure decrease in normotensive subjects because renin levels are normal.
7. CVD AND VITAMIN D The large cohort of the Intermountain Heart Collaborative Study Group reported a relationship between vitamin D levels and cardiovascular risk factors, disease status and incidental events. Low vitamin D status was associated with significant increases in the prevalence of diabetes, hypertension, hyperlipidemia, and peripheral vascular disease. In addition, vitamin D was also associated to coronary artery disease, myocardial infarction, heart failure, and stroke (Anderson et al., 2010). Serum 25(OH)D status is an independent risk factor for CVD. In the NHANES-III cohort CVD prevalence was higher in individuals with 25(OH)D levels below 20 ng ml1 as compared to those with higher levels (Kendrick et al., 2009). After adjusting for a long list of cofactors related to CVD, a strong and independent association emerged between 25(OH)D and CVD prevalence. After a 14-year follow up another recent NHANES-III report found that among Caucasians but not blacks fatal stroke was linked to low vitamin D levels (Michos, 2010). Serum 25(OH)D levels were measured in acute myocardial infarction patients enrolled in a 20-hospital US prospective registry. Serum 25(OH)D deficiency (20 ng ml1) was more common among non-Caucasian patients, and those with lower
389
390
F.R. Pérez-López et al.
social support, no insurance, diabetes, and less physical activity. Thus, vitamin D deficiency is present in almost all acute myocardial infarction patients (Lee et al., 2011). Reports indicate that low serum vitamin D levels may increase mortality risk due to CVD, cancer and other chronic diseases. It has been postulated, although not proven, that high endogenous vitamin D status could increase longevity (Pe´rez-Lo´pez et al., 2011). A meta-analysis reported that vitamin D (300–2000 IU day1; mean dose 528 IU) supplementation for an average of 5 or more years decreased risk for all-cause death by 7% (Autier and Gandini, 2007). The systematic review of prospective studies and randomized trials regarding calcium and/or vitamin D supplementation and subsequent cardiovascular events showed that vitamin D supplementation produces a nonsignificant reduction in CVD risk, whereas calcium or the vitamin D plus calcium supplementation had no effect (Wang et al., 2010).
8. FINAL REMARKS A significant proportion of the world population has low serum vitamin D levels which may negatively affect components of the METS and CVD associated conditions. The molecular mechanisms of these associations remain incompletely understood. Low sun exposure, use of sunscreens, changes in lifestyle, dietary habits, obesity, and other environmental factors contribute to hypovitaminosis D. The controversial puzzling results are due to complex metabolic mechanisms acting on the cardiocirculatory tree. Although vitamin D is not the health panacea, optimal vitamin D status should be a major task in order to improve health in the present generation. A traditional lifestyle with a vitamin D enriched natural diet, exposure to sunlight in a responsible manner and regular outdoor activities should be highly recommended. ‘Normal’ vitamin D levels required for optimal cell functioning are still unknown. In addition, causes of death may be confounded or poorly specified and hence result in bias. Nevertheless, low 25(OH)D levels do seem to be a marker of poor health. The ongoing Vitamin D and Omega-3 Trial (VITAL) will provide answers to many questions and hopefully confirm the benefits of vitamin D.
GLOSSARY Metabolic syndrome A cluster of metabolic risk factors including abdominal obesity, hypertension, insulin resistance, dyslipidemia, proinflammatory status, and increased thrombosis risk. Vitamin D A group of fat soluble secosteroids that exerts actions through both specific receptor and nongenomic mechanisms. Vitamin D receptor Cell structure that specifically binds vitamin D to initiate molecular changes.
Vitamin D and Cardiometabolic Risks
REFERENCES Anderson, J.L., May, H.T., Horne, B.D., et al., 2010. Intermountain Heart Collaborative (IHC) Study Group. Relation of vitamin D deficiency to cardiovascular risk factors, disease status, and incident events in a general healthcare population. The American Journal of Cardiology 106, 963–968. Autier, P., Gandini, S., 2007. Vitamin D supplementation and total mortality: a meta-analysis of randomized controlled trials. Archives of Internal Medicine 167, 1730–1737. Chandalia, M., Abate, N., 2007. Metabolic complications of obesity: inflated or inflamed? Journal of Diabetes and its Complications 21, 128–136. Chiu, K.C., Chu, A., Go, V.L., Saad, M.F., 2004. Hypovitaminosis D is associated with insulin resistance and beta cell dysfunction. American Journal of Clinical Nutrition 79, 820–825. Del Gobbo, L.C., Song, Y., Dannenbaum, D.A., Dewailly, E., Egeland, G.M., 2011. Serum 25-hydroxyvitamin D is not associated with insulin resistance or beta cell function in Canadian Cree. Journal of Nutrition 141, 290–295. Elks, C.M., Francis, J., 2010. Central adiposity, systemic inflammation, and the metabolic syndrome. Current Hypertension Reports 12, 99–104. Ford, E.S., Ajani, U.A., McGuire, L.C., Liu, S., 2005. Concentrations of serum vitamin D and the metabolic syndrome among U.S. adults. Diabetes Care 28, 1228–1230. Forouhi, N.G., Luan, J., Cooper, A., Boucher, B.J., Wareham, N.J., 2008. Baseline serum 25-hydroxy vitamin D is predictive of future glycemic status and insulin resistance: the Medical Research Council Ely Prospective Study 1990–2000. Diabetes 57, 2619–2625. Gannage´-Yared, M.H., Chedid, R., Khalife, S., et al., 2009. Vitamin D in relation to metabolic risk factors, insulin sensitivity and adiponectin in a young Middle-Eastern population. European Journal of Endocrinology 160, 965–971. Jorde, R., Figenschau, Y., Hutchinson, M., Emaus, N., Grimnes, G., 2010. High serum 25-hydroxyvitamin D concentrations are associated with a favorable serum lipid profile. European Journal of Clinical Nutrition 64, 1457–1464. Karhapa¨a¨, P., Pihlajama¨ki, J., Po¨rsti, I., et al., 2010. Diverse associations of 25-hydroxyvitamin D and 1,25-dihydroxy-vitamin D with dyslipidaemias. Journal of Internal Medicine 268, 604–610. Kayaniyil, S., Vieth, R., Harris, S.B., et al., 2011. Association of 25(OH)D and PTH with metabolic syndrome and its traditional and nontraditional components. Journal of Clinical Endocrinology and Metabolism 96, 168–175. Kendrick, J., Targher, G., Smits, G., Chonchol, M., 2009. 25-Hydroxyvitamin D deficiency is independently associated with cardiovascular disease in the Third National Health and Nutrition Examination Survey. Atherosclerosis 205, 255–260. Lee, J.H., Gadi, R., Spertus, J.A., Tang, F., O’ Keefe, J.H., 2011. Prevalence of vitamin D deficiency in patients with acute myocardial infarction. The American Journal of Cardiology 107 (11), 1636–1638. Liu, E., Meigs, J.B., Pittas, A.G., et al., 2009. Plasma 25-hydroxyvitamin D is associated with markers of the insulin resistant phenotype in nondiabetic adults. Journal of Nutrition 139, 329–334. Looker, A.C., Pfeiffer, C.M., Lacher, D.A., et al., 2008. Serum 25-hydroxyvitamin D status of the US population: 1988–1994 compared with 2000–2004. American Journal of Clinical Nutrition 88, 1519–1527. McGill, A.T., Stewart, J.M., Lithander, F.E., Strik, C.M., Poppitt, S.D., 2008. Relationships of low serum vitamin D3 with anthropometry and markers of the metabolic syndrome and diabetes in overweight and obesity. Nutrition Journal 7, 4. Michos, E., 2010. Vitamin-D deficiency linked to fatal stroke in whites but not blacks. Risk of fatal stroke associated with vitamin-D deficiency (25[OH]D <15 ng/mL) in white vs black participants. Available from: http://www.theheart.org/article/1149285.do (accessed 30 March 2011). Parikh, S.J., Edelman, M., Uwaifo, G.I., et al., 2004. The relationship between obesity and serum 1,25-dihydroxy vitamin D concentrations in healthy adults. Journal of Clinical Endocrinology and Metabolism 89, 1196–1199. Pe´rez-Lo´pez, F.R., 2009. Vitamin D metabolism and cardiovascular risk factors in postmenopausal women. Maturitas 62, 248–262.
391
392
F.R. Pérez-López et al.
Pe´rez-Lo´pez, F.R., Chedraui, P., Ferna´ndez-Alonso, A.M., 2011. Vitamin D and aging: beyond calcium and bone metabolism. Maturitas 69, 27–36. Pittas, A.G., Chung, M., Trikalinos, T., et al., 2010. Systematic review: vitamin D and cardiometabolic outcomes. Annals of Internal Medicine 152, 307–314. Scragg, R., Sowers, M., Bell, C., 2007. Serum 25-hydroxyvitamin D, ethnicity, and blood pressure in the Third National Health and Nutrition Examination Survey. American Journal of Hypertension 20, 713–719. Tai, K., Need, A.G., Horowitz, M., Chapman, I.M., 2008. Glucose tolerance and vitamin D: effects of treating vitamin D deficiency. Nutrition 24, 950–956. Targher, G., Bertolini, L., Padovani, R., et al., 2006. Serum 25-hydroxyvitamin D3 concentrations and carotid artery intima-media thickness among type 2 diabetic patients. Clinical Endocrinology 65, 593–597. Vieth, R., 1999. Vitamin D supplementation, 25-hydroxyvitamin D concentrations, and safety. American Journal of Clinical Nutrition 69, 842–856. Wang, L., Manson, J.E., Song, Y., Sesso, H.D., 2010. Systematic review: vitamin D and calcium supplementation in prevention of cardiovascular events. Annals of Internal Medicine 152, 315–323. Yiu, Y.F., Chan, Y.H., Yiu, K.H., et al., 2011. Vitamin D deficiency is associated with depletion of circulating endothelial progenitor cells and endothelial dysfunction in patients with type 2 diabetes. Journal of Clinical Endocrinology and Metabolism 8 (1), 47–52.
FURTHER READING Bischoff-Ferrari, H.A., Shao, A., Dawson-Hughes, B., 2010. Benefit-risk assessment of vitamin D supplementation. Osteoporosis International 21, 1121–1132.http://www.ncbi.nlm.nih.gov/pmc/articles/ PMC3062161/pdf/nihms-280261.pdf. Grant, W.B., 2009. In defense of the sun: an estimate of changes in mortality rates in the United States if mean serum 25-hydroxyvitamin D levels were raised to 45 ng/mL by solar ultraviolet-B irradiance. Dermatoendocrinol 1, 207–214. Kulie, T., Groff, A., Redmer, J., Hounshell, J., Schrager, S., 2009. Vitamin D: an evidence-based review. Journal of the American Board of Family Medicine 22, 698–706.http://www.jabfm.org/cgi/ pmidlookup?view¼long&pmid¼19897699. Manson, J.E., 2010. Vitamin D and the heart: why we need large-scale clinical trials. Cleveland Clinic Journal of Medicine 77, 903–910.http://www.ccjm.org/content/77/12/903.full.pdfþhtml. Ross, A.C., Manson, J.E., Abrams, S.A., et al., 2011. The 2011 report on dietary reference intakes for calcium and vitamin D from the Institute of Medicine: what clinicians need to know. Journal of Clinical Endocrinology and Metabolism 96, 53–58.http://www.ncbi.nlm.nih.gov/pmc/articles/ PMC3046611/?tool¼pubmed.
Relevant Websites http://www.iom.edu/Reports/2010/Dietary-Reference-Intakes-for-Calcium-and-Vitamin-D.aspx – Institute of Medicine. Dietary reference intakes for calcium and vitamin D. http://ods.od.nih.gov/factsheets/vitamind/ – National Institutes of health. Office of Dietary Supplements. Vitamin D. http://www.naturaldatabase.com – Natural Medicines. Comprehensive database. Vitamin D. http://www.vitamindsociety.org/ – The Vitamin D Society. http://www.vitamindcouncil.org/ – Vitamin D council.