- Email: [email protected]
Vitamin D and Cardiovascular Disease
Journal of the American College of Cardiology © 2011 by the American College of Cardiology Foundation Published by Elsevier Inc.
EDITORIAL COMMENT
Vitamin D and Cardiovascular Disease Time for Large Randomized Trials* Carlos A. Camargo, JR, MD, DRPH Boston, Massachusetts
Vitamin D is a hormone of critical importance to calcium homeostasis and bone health (1). Although widely regarded as a vitamin, a more accurate term is “conditional vitamin,” in that vitamin D is required in the diet only when the skin does not make enough through the action of ultraviolet B radiation from the sun. At higher latitudes (e.g., most of the United States, all of Canada and Europe, southern Australia, and all of New Zealand), ultraviolet B exposure drops dramatically during autumn and winter (2). Although it is certainly possible to produce and store sufficient vitamin D after abundant sunlight exposure in spring and summer, indoor life-styles and sun avoidance campaigns have decreased such exposure and led many to require ingestion of this unique hormone/vitamin. See page 1433
Over the past decade, a growing body of evidence suggests that the health effects of vitamin D extend beyond rickets and bone health (2). Although it would be preferable to know local (even intracellular) levels of the active hormone (i.e., 1,25-dihydroxyvitamin D), circulating levels of the precursor, 25-hydroxyvitamin D (25-OHD), remain the best available method of measuring overall vitamin D status. The recommended level of serum 25-OHD is highly controversial, with some recommending a level of 20 ng/ml or higher (3) while others recommend a level of at least 30 ng/ml (4,5) or much higher (6). However, using either the 20 or 30 ng/ml threshold, national studies clearly document low serum 25-OHD levels for a substantial segment of the U.S. population, particularly among racial and ethnic minorities (7). Of particular interest to cardiovascular researchers and clinicians is growing evidence of a link between low vitamin
*Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology. From Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts. Dr. Camargo is supported in part by the Massachusetts General Hospital Center for D-Receptor Activation Research.
Vol. 58, No. 14, 2011 ISSN 0735-1097/$36.00 doi:10.1016/j.jacc.2011.06.037
D and increased risk for cardiovascular disease (CVD) (8). Although this may seem like a recent development, the origins of this hypothesis actually go back a few decades. In 1981 Scragg (9) drew on ecological studies of variations in CVD by season, latitude, and altitude and published a hypothesis that sunlight and vitamin D may protect against CVD. In 1990, Scragg et al. (10) reported a populationbased case-control study from New Zealand that found a strong inverse association between plasma 25-OHD level and risk for myocardial infarction (10). Over the past 5 years, there has been renewed interest in this hypothesis, with supportive evidence from several large prospective cohort studies (11), including analyses that focused on older adults (12). Indeed, the original hypothesis about myocardial infarction has now expanded to include atherosclerosis, heart failure, stroke, and several cardiometabolic disorders (e.g., hypertension, diabetes). Although an explanation for these diverse “effects” remains unclear, it undoubtedly involves multiple mechanisms. The growing enthusiasm for vitamin D deficiency as an important, common, and easily treatable CVD risk factor (8) has been offset recently by skepticism about vitamin D as a panacea, a view reflected in a 2011 report from the Institute of Medicine (3). In brief, skeptics wonder if vitamin D status is simply a marker of general health. In other words, do healthier people tend to spend more time outside, resulting in more ultraviolet B exposure and thus higher 25-OHD levels? In such a scenario, confounding by better baseline health (or outdoor activity) would account for the positive findings in recent epidemiologic studies. If the association between vitamin D and CVD is truly confounded in this manner, the initiation of vitamin D supplements might yield little (if any) impact on CVD risk. In this issue of the Journal, Kestenbaum et al. (13) examine the associations of 25-OHD, parathyroid hormone (PTH), and incident CVD in the Cardiovascular Health Study. In 2,312 older adults who were free of CVD at baseline, 17% had baseline 25-OHD levels ⬍15 ng/ml, and 25% had baseline PTH levels ⱖ65 pg/ml. In brief, the investigators found that baseline levels of 25-OHD were inversely associated with risk for myocardial infarction and all-cause mortality, while PTH excess was associated with heart failure. Although statistical power was limited, they found no evidence of an interaction between 25-OHD and PTH levels and cardiovascular events. These findings support those who believe that low vitamin D is a modifiable risk factor for at least some types of CVD, such as myocardial infarction, and also raise the possibility that vitamin D and PTH might influence CVD risk through divergent pathways, at least in this population of older adults without baseline CVD and ⬍1% baseline use of vitamin D supplements. With regard to the confounding, the investigators had data on all of the traditional CVD risk factors, including physical activity, and multivariate analyses adjusted for these
Camargo, Jr Vitamin D and CVD
JACC Vol. 58, No. 14, 2011 September 27, 2011:1442–4
factors. Although it remains possible that residual confounding is responsible for the observed associations, it is also possible that an observed association is both causal and confounded. In other words, even a demonstrably confounded association might be true. Although multivariate analysis would begin to address confounding, other methodologic limitations (e.g., the use of a single measure to look at 14-year outcomes) probably obscured real associations. The final odds ratio reflects a complex mixture of causality, bias and confounding. Notwithstanding these familiar epidemiologic challenges, the findings are generally consistent with those of prior studies. For example, the all-cause mortality finding (a 9% increase for every 10 ng/ml decrease in 25-OHD) matches a meta-analysis of bone health randomized controlled trials (RCTs) comparing vitamin D with placebo, in which vitamin D supplementation yielded a 7% reduction in all-cause mortality (14). The investigators’ suggestion that vitamin D and PTH may affect CVD risk through divergent pathways requires further study. Although it is likely that these hormones have more (or less) impact on specific outcomes, PTH represents an endogenous biologic marker of inadequate vitamin D; it seems highly likely that there would be some overlap. Although it is tempting to conclude that PTH is uniquely associated with heart failure, other studies suggest that vitamin D plays an important role in the pathogenesis and clinical course of heart failure (15,16). It is possible that PTH plays a predominant role in some populations, but I doubt that this is an all-or-none phenomenon. Further epidemiologic studies are needed to clarify this issue. More important, the field needs insights from 2 other types of research: 1) translational research to improve understanding of potential mechanisms for the emerging epidemiologic associations; and 2) large, population-based RCTs to formally test causality in humans. Already, 2 such trials are under way (Table 1): the ViDA (Vitamin D Assessment) trial in New Zealand and the VITAL (Vitamin D and Omega-3 Trial) in the United States. The 2 RCTs are sufficiently different that they should provide complementary answers to the major question, Does the initiation of vitamin D supplementation prevent CVD? The design
1443
and implementation of additional population-based RCTs would help address the impact of other vitamin D regimens in different populations. Unfortunately, these trials will take several years to complete. In the meantime, in the absence of RCT evidence, it is difficult to draw conclusions about the cardiovascular benefits of vitamin D supplementation (3). Even for those at lower 25-OHD levels, there is controversy about the 25-OHD target for optimal general health, with several discordant recommendations in the published research (3– 6). On the basis of my review of the available data, I believe that the optimal 25-OHD level for most health problems will be around 40 ng/ml (100 nmol/l), with relatively small differences found in the range of 35 to 50 ng/ml. I also submit that it will be easier to demonstrate benefit by elevating a person’s 25-OHD from, for example, 10 to 20 ng/ml, compared to elevating another person’s 25-OHD from 40 to 50 ng/ml; baseline levels of 25-OHD have to matter. Although this may seem like a commonsense observation, the role of baseline vitamin status in RCTs continues to receive inadequate attention in scientific circles (17). Last, given the many factors that affect vitamin D status (e.g., latitude, season, sunlight exposure, skin color, obesity, genetics), the search for a “one-size-fits-all” regimen seems misguided. Although RCTs need to test specific doses because of the ethical challenge of testing baseline 25-OHD and then assigning someone with established (albeit asymptomatic) vitamin D deficiency to placebo, it is unclear why supplementation of individual patients should be restricted to a fixed regimen. In summary, for those who believe that the inverse association between vitamin D and CVD risk is probably causal, and that the association will prove modifiable, the next steps are clear: widespread serum 25-OHD testing and vitamin D supplementation to achieve a specific 25-OHD target. For those who are more skeptical of epidemiologic associations, who have concerns about adding unjustified costs to an already burdened health system, or who worry that supplementation may cause unintended harm—as has happened with antioxidant interventions (18)—the next steps are equally clear: the imperative of completing large
on the Population-Based, Large, Health Effects of Vitamin Randomized, D Supplementation Double-Blind,Double-Blind, (as Placebo-Controlled of AugustPlacebo-Controlled 2011)Trials Large, Population-Based, Randomized, Trials Table 1 on the Health Effects of Vitamin D Supplementation (as of August 2011) ViDA Country
New Zealand
Principal investigator(s)
Scragg and Camargo
Target sample size
VITAL United States Manson and Buring
5,100
20,000
Age range
50–84 yrs (both men and women)
Men: ⱖ50 yrs; women: ⱖ55 yrs
Vitamin D3 intervention
100,000 IU/month (about 3,300 IU/day); subjects also are given an extra 100,000 IU at the start of the trial and every autumn
2,000 IU/day; part of a 2 ⫻ 2 factorial trial in which the other intervention is 1 g/day of specific omega-3 fatty acids
Primary outcomes
CVD, infection, fractures
Cancer, CVD
Year enrollment started
2011
Expected year of results
2017
Trial registration
ACTRN12611000402943
CVD ⫽ cardiovascular disease; ViDA ⫽ Vitamin D Assessment trial; VITAL ⫽ Vitamin D and Omega-3 Trial.
2011 2017 NCT01169259
1444
Camargo, Jr Vitamin D and CVD
RCTs to justify changes in clinical practice and health policy. In a few years, ViDA and VITAL will begin to shed a light on this important and controversial issue. Reprint requests and correspondence: Dr. Carlos A. Camargo, Massachusetts General Hospital, 326 Cambridge Street, Suite 410, Boston, Massachusetts 02114. E-mail: [email protected].
REFERENCES
1. Feldman D, Pike JW, Adams JS. Vitamin D. 3rd edition. Amsterdam, the Netherlands: Elsevier Academic Press, 2011. 2. Holick MF. Vitamin D deficiency. N Engl J Med 2007;357:266 – 81. 3. Institute of Medicine. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: National Academies Press, 2011. 4. Canadian Paediatric Society. Vitamin D supplementation: recommendations for Canadian mothers and infants (position statement FNIM 2007-01). Paediatr Child Health 2007;12:583–9. 5. Hanley DA, Cranney A, Jones G, Whiting SJ, Leslie WD. Vitamin D in adult health and disease: a review and guideline statement from Osteoporosis Canada (summary). CMAJ 2010;182:1315–9. 6. Garland CF, French CB, Baggerly LL, Heaney RP. Vitamin D supplement doses and serum 25-hydroxyvitamin D in the range associated with cancer prevention. Anticancer Res 2011;31:607–11. 7. Looker AC, Johnson CL, Lacher DA, Pfeiffer CM, Schleicher RL, Sempos CT. Vitamin D status: United States, 2001–2006. NCHS Data Brief 2011:1– 8. 8. Lee JH, O’Keefe JH, Bell D, Hensrud DD, Holick MF. Vitamin D deficiency an important, common, and easily treatable cardiovascular risk factor? J Am Coll Cardiol 2008;52:1949 –56.
JACC Vol. 58, No. 14, 2011 September 27, 2011:1442–4 9. Scragg R. Seasonality of cardiovascular disease mortality and the possible protective effect of ultra-violet radiation. Int J Epidemiol 1981;10:337– 41. 10. Scragg R, Jackson R, Holdaway IM, Lim T, Beaglehole R. Myocardial infarction is inversely associated with plasma 25hydroxyvitamin D3 levels: a community-based study. Int J Epidemiol 1990;19:559 – 63. 11. Grandi NC, Breitling LP, Brenner H. Vitamin D and cardiovascular disease: systematic review and meta-analysis of prospective studies. Prev Med 2010;51:228 –33. 12. Ginde AA, Scragg R, Schwartz RS, Camargo CA Jr. Prospective study of serum 25-hydroxyvitamin D level, cardiovascular disease mortality, and all-cause mortality in older U.S. adults. J Am Geriatr Soc 2009;57:1595– 603. 13. Kestenbaum B, Katz R, de Boer I, et al. Vitamin D, parathyroid hormone, and cardiovascular events among older adults. J Am Coll Cardiol 2011;58:1433– 41. 14. Autier P, Gandini S. Vitamin D supplementation and total mortality: a meta-analysis of randomized controlled trials. Arch Intern Med 2007;167:1730 –7. 15. Bae S, Yalamarti B, Ke Q, et al. Preventing progression of cardiac hypertrophy and development of heart failure by paricalcitol therapy in rats. Cardiovasc Res 2011;91:632–9. 16. Liu LC, Voors AA, van Veldhuisen DJ, et al. Vitamin D status and outcomes in heart failure patients. Eur J Heart Fail 2011;13:619 –25. 17. Morris MC, Tangney CC. A potential design flaw of randomized trials of vitamin supplements. JAMA 2011;305:1348 –9. 18. Bjelakovic G, Nikolova D, Gluud LL, Simonetti RG, Gluud C. Mortality in randomized trials of antioxidant supplements for primary and secondary prevention: systematic review and meta-analysis. JAMA 2007;297:842–57. Key Words: heart failure y mineral metabolism y myocardial infarction y parathyroid hormone y vitamin D.
EDITORIAL COMMENT
Vitamin D and Cardiovascular Disease Time for Large Randomized Trials* Carlos A. Camargo, JR, MD, DRPH Boston, Massachusetts
Vitamin D is a hormone of critical importance to calcium homeostasis and bone health (1). Although widely regarded as a vitamin, a more accurate term is “conditional vitamin,” in that vitamin D is required in the diet only when the skin does not make enough through the action of ultraviolet B radiation from the sun. At higher latitudes (e.g., most of the United States, all of Canada and Europe, southern Australia, and all of New Zealand), ultraviolet B exposure drops dramatically during autumn and winter (2). Although it is certainly possible to produce and store sufficient vitamin D after abundant sunlight exposure in spring and summer, indoor life-styles and sun avoidance campaigns have decreased such exposure and led many to require ingestion of this unique hormone/vitamin. See page 1433
Over the past decade, a growing body of evidence suggests that the health effects of vitamin D extend beyond rickets and bone health (2). Although it would be preferable to know local (even intracellular) levels of the active hormone (i.e., 1,25-dihydroxyvitamin D), circulating levels of the precursor, 25-hydroxyvitamin D (25-OHD), remain the best available method of measuring overall vitamin D status. The recommended level of serum 25-OHD is highly controversial, with some recommending a level of 20 ng/ml or higher (3) while others recommend a level of at least 30 ng/ml (4,5) or much higher (6). However, using either the 20 or 30 ng/ml threshold, national studies clearly document low serum 25-OHD levels for a substantial segment of the U.S. population, particularly among racial and ethnic minorities (7). Of particular interest to cardiovascular researchers and clinicians is growing evidence of a link between low vitamin
*Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology. From Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts. Dr. Camargo is supported in part by the Massachusetts General Hospital Center for D-Receptor Activation Research.
Vol. 58, No. 14, 2011 ISSN 0735-1097/$36.00 doi:10.1016/j.jacc.2011.06.037
D and increased risk for cardiovascular disease (CVD) (8). Although this may seem like a recent development, the origins of this hypothesis actually go back a few decades. In 1981 Scragg (9) drew on ecological studies of variations in CVD by season, latitude, and altitude and published a hypothesis that sunlight and vitamin D may protect against CVD. In 1990, Scragg et al. (10) reported a populationbased case-control study from New Zealand that found a strong inverse association between plasma 25-OHD level and risk for myocardial infarction (10). Over the past 5 years, there has been renewed interest in this hypothesis, with supportive evidence from several large prospective cohort studies (11), including analyses that focused on older adults (12). Indeed, the original hypothesis about myocardial infarction has now expanded to include atherosclerosis, heart failure, stroke, and several cardiometabolic disorders (e.g., hypertension, diabetes). Although an explanation for these diverse “effects” remains unclear, it undoubtedly involves multiple mechanisms. The growing enthusiasm for vitamin D deficiency as an important, common, and easily treatable CVD risk factor (8) has been offset recently by skepticism about vitamin D as a panacea, a view reflected in a 2011 report from the Institute of Medicine (3). In brief, skeptics wonder if vitamin D status is simply a marker of general health. In other words, do healthier people tend to spend more time outside, resulting in more ultraviolet B exposure and thus higher 25-OHD levels? In such a scenario, confounding by better baseline health (or outdoor activity) would account for the positive findings in recent epidemiologic studies. If the association between vitamin D and CVD is truly confounded in this manner, the initiation of vitamin D supplements might yield little (if any) impact on CVD risk. In this issue of the Journal, Kestenbaum et al. (13) examine the associations of 25-OHD, parathyroid hormone (PTH), and incident CVD in the Cardiovascular Health Study. In 2,312 older adults who were free of CVD at baseline, 17% had baseline 25-OHD levels ⬍15 ng/ml, and 25% had baseline PTH levels ⱖ65 pg/ml. In brief, the investigators found that baseline levels of 25-OHD were inversely associated with risk for myocardial infarction and all-cause mortality, while PTH excess was associated with heart failure. Although statistical power was limited, they found no evidence of an interaction between 25-OHD and PTH levels and cardiovascular events. These findings support those who believe that low vitamin D is a modifiable risk factor for at least some types of CVD, such as myocardial infarction, and also raise the possibility that vitamin D and PTH might influence CVD risk through divergent pathways, at least in this population of older adults without baseline CVD and ⬍1% baseline use of vitamin D supplements. With regard to the confounding, the investigators had data on all of the traditional CVD risk factors, including physical activity, and multivariate analyses adjusted for these
Camargo, Jr Vitamin D and CVD
JACC Vol. 58, No. 14, 2011 September 27, 2011:1442–4
factors. Although it remains possible that residual confounding is responsible for the observed associations, it is also possible that an observed association is both causal and confounded. In other words, even a demonstrably confounded association might be true. Although multivariate analysis would begin to address confounding, other methodologic limitations (e.g., the use of a single measure to look at 14-year outcomes) probably obscured real associations. The final odds ratio reflects a complex mixture of causality, bias and confounding. Notwithstanding these familiar epidemiologic challenges, the findings are generally consistent with those of prior studies. For example, the all-cause mortality finding (a 9% increase for every 10 ng/ml decrease in 25-OHD) matches a meta-analysis of bone health randomized controlled trials (RCTs) comparing vitamin D with placebo, in which vitamin D supplementation yielded a 7% reduction in all-cause mortality (14). The investigators’ suggestion that vitamin D and PTH may affect CVD risk through divergent pathways requires further study. Although it is likely that these hormones have more (or less) impact on specific outcomes, PTH represents an endogenous biologic marker of inadequate vitamin D; it seems highly likely that there would be some overlap. Although it is tempting to conclude that PTH is uniquely associated with heart failure, other studies suggest that vitamin D plays an important role in the pathogenesis and clinical course of heart failure (15,16). It is possible that PTH plays a predominant role in some populations, but I doubt that this is an all-or-none phenomenon. Further epidemiologic studies are needed to clarify this issue. More important, the field needs insights from 2 other types of research: 1) translational research to improve understanding of potential mechanisms for the emerging epidemiologic associations; and 2) large, population-based RCTs to formally test causality in humans. Already, 2 such trials are under way (Table 1): the ViDA (Vitamin D Assessment) trial in New Zealand and the VITAL (Vitamin D and Omega-3 Trial) in the United States. The 2 RCTs are sufficiently different that they should provide complementary answers to the major question, Does the initiation of vitamin D supplementation prevent CVD? The design
1443
and implementation of additional population-based RCTs would help address the impact of other vitamin D regimens in different populations. Unfortunately, these trials will take several years to complete. In the meantime, in the absence of RCT evidence, it is difficult to draw conclusions about the cardiovascular benefits of vitamin D supplementation (3). Even for those at lower 25-OHD levels, there is controversy about the 25-OHD target for optimal general health, with several discordant recommendations in the published research (3– 6). On the basis of my review of the available data, I believe that the optimal 25-OHD level for most health problems will be around 40 ng/ml (100 nmol/l), with relatively small differences found in the range of 35 to 50 ng/ml. I also submit that it will be easier to demonstrate benefit by elevating a person’s 25-OHD from, for example, 10 to 20 ng/ml, compared to elevating another person’s 25-OHD from 40 to 50 ng/ml; baseline levels of 25-OHD have to matter. Although this may seem like a commonsense observation, the role of baseline vitamin status in RCTs continues to receive inadequate attention in scientific circles (17). Last, given the many factors that affect vitamin D status (e.g., latitude, season, sunlight exposure, skin color, obesity, genetics), the search for a “one-size-fits-all” regimen seems misguided. Although RCTs need to test specific doses because of the ethical challenge of testing baseline 25-OHD and then assigning someone with established (albeit asymptomatic) vitamin D deficiency to placebo, it is unclear why supplementation of individual patients should be restricted to a fixed regimen. In summary, for those who believe that the inverse association between vitamin D and CVD risk is probably causal, and that the association will prove modifiable, the next steps are clear: widespread serum 25-OHD testing and vitamin D supplementation to achieve a specific 25-OHD target. For those who are more skeptical of epidemiologic associations, who have concerns about adding unjustified costs to an already burdened health system, or who worry that supplementation may cause unintended harm—as has happened with antioxidant interventions (18)—the next steps are equally clear: the imperative of completing large
on the Population-Based, Large, Health Effects of Vitamin Randomized, D Supplementation Double-Blind,Double-Blind, (as Placebo-Controlled of AugustPlacebo-Controlled 2011)Trials Large, Population-Based, Randomized, Trials Table 1 on the Health Effects of Vitamin D Supplementation (as of August 2011) ViDA Country
New Zealand
Principal investigator(s)
Scragg and Camargo
Target sample size
VITAL United States Manson and Buring
5,100
20,000
Age range
50–84 yrs (both men and women)
Men: ⱖ50 yrs; women: ⱖ55 yrs
Vitamin D3 intervention
100,000 IU/month (about 3,300 IU/day); subjects also are given an extra 100,000 IU at the start of the trial and every autumn
2,000 IU/day; part of a 2 ⫻ 2 factorial trial in which the other intervention is 1 g/day of specific omega-3 fatty acids
Primary outcomes
CVD, infection, fractures
Cancer, CVD
Year enrollment started
2011
Expected year of results
2017
Trial registration
ACTRN12611000402943
CVD ⫽ cardiovascular disease; ViDA ⫽ Vitamin D Assessment trial; VITAL ⫽ Vitamin D and Omega-3 Trial.
2011 2017 NCT01169259
1444
Camargo, Jr Vitamin D and CVD
RCTs to justify changes in clinical practice and health policy. In a few years, ViDA and VITAL will begin to shed a light on this important and controversial issue. Reprint requests and correspondence: Dr. Carlos A. Camargo, Massachusetts General Hospital, 326 Cambridge Street, Suite 410, Boston, Massachusetts 02114. E-mail: [email protected].
REFERENCES
1. Feldman D, Pike JW, Adams JS. Vitamin D. 3rd edition. Amsterdam, the Netherlands: Elsevier Academic Press, 2011. 2. Holick MF. Vitamin D deficiency. N Engl J Med 2007;357:266 – 81. 3. Institute of Medicine. Dietary Reference Intakes for Calcium and Vitamin D. Washington, DC: National Academies Press, 2011. 4. Canadian Paediatric Society. Vitamin D supplementation: recommendations for Canadian mothers and infants (position statement FNIM 2007-01). Paediatr Child Health 2007;12:583–9. 5. Hanley DA, Cranney A, Jones G, Whiting SJ, Leslie WD. Vitamin D in adult health and disease: a review and guideline statement from Osteoporosis Canada (summary). CMAJ 2010;182:1315–9. 6. Garland CF, French CB, Baggerly LL, Heaney RP. Vitamin D supplement doses and serum 25-hydroxyvitamin D in the range associated with cancer prevention. Anticancer Res 2011;31:607–11. 7. Looker AC, Johnson CL, Lacher DA, Pfeiffer CM, Schleicher RL, Sempos CT. Vitamin D status: United States, 2001–2006. NCHS Data Brief 2011:1– 8. 8. Lee JH, O’Keefe JH, Bell D, Hensrud DD, Holick MF. Vitamin D deficiency an important, common, and easily treatable cardiovascular risk factor? J Am Coll Cardiol 2008;52:1949 –56.
JACC Vol. 58, No. 14, 2011 September 27, 2011:1442–4 9. Scragg R. Seasonality of cardiovascular disease mortality and the possible protective effect of ultra-violet radiation. Int J Epidemiol 1981;10:337– 41. 10. Scragg R, Jackson R, Holdaway IM, Lim T, Beaglehole R. Myocardial infarction is inversely associated with plasma 25hydroxyvitamin D3 levels: a community-based study. Int J Epidemiol 1990;19:559 – 63. 11. Grandi NC, Breitling LP, Brenner H. Vitamin D and cardiovascular disease: systematic review and meta-analysis of prospective studies. Prev Med 2010;51:228 –33. 12. Ginde AA, Scragg R, Schwartz RS, Camargo CA Jr. Prospective study of serum 25-hydroxyvitamin D level, cardiovascular disease mortality, and all-cause mortality in older U.S. adults. J Am Geriatr Soc 2009;57:1595– 603. 13. Kestenbaum B, Katz R, de Boer I, et al. Vitamin D, parathyroid hormone, and cardiovascular events among older adults. J Am Coll Cardiol 2011;58:1433– 41. 14. Autier P, Gandini S. Vitamin D supplementation and total mortality: a meta-analysis of randomized controlled trials. Arch Intern Med 2007;167:1730 –7. 15. Bae S, Yalamarti B, Ke Q, et al. Preventing progression of cardiac hypertrophy and development of heart failure by paricalcitol therapy in rats. Cardiovasc Res 2011;91:632–9. 16. Liu LC, Voors AA, van Veldhuisen DJ, et al. Vitamin D status and outcomes in heart failure patients. Eur J Heart Fail 2011;13:619 –25. 17. Morris MC, Tangney CC. A potential design flaw of randomized trials of vitamin supplements. JAMA 2011;305:1348 –9. 18. Bjelakovic G, Nikolova D, Gluud LL, Simonetti RG, Gluud C. Mortality in randomized trials of antioxidant supplements for primary and secondary prevention: systematic review and meta-analysis. JAMA 2007;297:842–57. Key Words: heart failure y mineral metabolism y myocardial infarction y parathyroid hormone y vitamin D.