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Vitamin D Status and the Risk of Cardiovascular Disease Death. Kilkkinen A, Knekt P, Aro A, Rissanen H, Marniemi J, Heliövaara M, Impivaara O, Reunanen A. Am J Epidemiol. 2009 Sep 17. [Epub ahead of print] PMID: 19762371 doi:10.1093/aje/kwp227 A low vitamin D level may be associated with higher risk of a fatal CVD event, particularly cerebrovascular death. These findings need to be replicated in other populations. To demonstrate a causal link between vitamin D and CVD, randomized controlled trials are required.

Prospective Study of Serum 25-Hydroxyvitamin D Level, Cardiovascular Disease Mortality, and All-Cause Mortality in Older U.S. Adults. Ginde AA, Scragg R, Schwartz RS, Camargo CA Jr. J Am Geriatr Soc. 2009 Jun 22. [Epub ahead of print] PMID: 19549021 DOI: 10.1111/j.1532-5415.2009.02359.x CONCLUSION: In noninstitutionalized older adults, a group at high risk for all-cause mortality, serum 25(OH)D levels had an independent, inverse association with CVD and all-cause mortality. Randomized controlled trials of vitamin D supplementation in older adults are warranted to determine whether this association is causal and reversible.

Strong correlations have been noted between cardiovascular diseases and low bone density / osteoporosis-connections so strong that the presence of one is considered a likely predictor of the other. This relationship has led to the hypothesis that these conditions share core pathophysiological mechanisms. Recent advances in our understanding of the complimentary roles played by vitamin D3 and vitamin K2 in vascular and bone health provide support for this hypothesis, along with insight into key metabolic dysfunctions underlying cardiovascular disease and osteoporosis. Part II, The Vitamin K Connection to Cardiovascular Health, reviews the ways in which vitamin K regulates calcium utlization, preventing vascular and soft tissue calcification while complimenting the bone-building actions of vitamin D, and also discusses vitamin K safety and dosage issues, and the necessity of providing vitamin K and vitamin A along with vitamin D to preclude adverse effects associated with hypervitaminosis D.

Strong correlations have been noted between cardiovascular diseases and low bone density / osteoporosis-connections so strong that the presence of one type of pathology is considered a likely predictor of the other. This potentially causal relationship has led to the hypothesis that these conditions share core mechanisms. Recent advances in our understanding of the complimentary roles played by vitamin D3 and vitamin K2 in vascular and bone health provide support for this hypothesis, along with insight into key metabolic dysfunctions underlying cardiovascular disease and osteoporosis. Part I of this review summarizes current research linking vitamin D deficiency to cardiovascular disease, the physiological mechanisms underlying vitamin D's cardiovascular effects, and leading vitamin D researchers' recommendations for significantly higher supplemental doses of the pro-hormone. Part II reviews the vitamin K connection to cardiovascular disease; the ways in which vitamin D and vitamin K pair up to prevent inflammation, vascular calcification and osteoporosis; and the necessity of providing vitamin K along with vitamin D to preclude adverse effects associated with hypervitaminosis D, which include vascular and other soft tissue calcification.

"March 18, 2009 | Marlene Busko Palm Harbor, FL - In a large study of adolescents, low serum levels of 25-dihydroxyvitamin D (25[OH]D) strongly predicted prevalence of hypertension, hyperglycemia, and metabolic syndrome [1]. The findings were reported at the AHA 49th Annual Conference on Cardiovascular Disease Epidemiology and Prevention. Adolescents with vitamin-D levels in the lowest quartile were almost four times more likely to have metabolic syndrome than those with vitamin-D levels in the highest quartile. "I think that is quite alarming," lead author Dr Jared P Reis (Johns Hopkins Medical Institutions, Baltimore, MD) said in an AHA podcast issued to the media."

25-hydroxyvitamin D levels inversely associate with risk for developing coronary artery calcification. de Boer IH, Kestenbaum B, Shoben AB, Michos ED, Sarnak MJ, Siscovick DS. J Am Soc Nephrol. 2009 Aug;20(8):1805-12. Epub 2009 May 14. PMID: 19443637 doi: 10.1681/ASN.2008111157 "In conclusion, lower 25-hydroxyvitamin D concentrations associate with increased risk for incident CAC. Accelerated development of atherosclerosis may underlie, in part, the increased cardiovascular risk associated with vitamin D deficiency."

Effect of vitamin D deficiency and replacement on endothelial function in asymptomatic subjects. Tarcin O, Yavuz DG, Ozben B, Telli A, Velioglu Ogunc A, Yuksel M, Toprak A, Yazici D, Sancak S, Deyneli O, Akalin S. J Clin Endocrinol Metab. 2009 Jul 7. [Epub ahead of print] PMID: 19584181 doi:10.1210/jc.2008-1212 Conclusions: This study shows that 25(OH)D deficiency is associated with endothelial dysfunction and increased lipid peroxidation. Replacement of vitamin D has favorable effects on endothelial function. Vitamin D deficiency can be seen as an independent risk factor of atherosclerosis. Hypovitaminosis D associated endothelial dysfunction may predispose to higher cardiovascular disease in the winter.

Vitamin D in preventive medicine: are we ignoring the evidence? Zittermann A. Br J Nutr. 2003 May;89(5):552-72. Review. PMID: 12720576 Vitamin D is metabolised by a hepatic 25-hydroxylase into 25-hydroxyvitamin D (25(OH)D) and by a renal 1alpha-hydroxylase into the vitamin D hormone calcitriol. Calcitriol receptors are present in more than thirty different tissues. Apart from the kidney, several tissues also possess the enzyme 1alpha-hydroxylase, which is able to use circulating 25(OH)D as a substrate. Serum levels of 25(OH)D are the best indicator to assess vitamin D deficiency, insufficiency, hypovitaminosis, adequacy, and toxicity. European children and young adults often have circulating 25(OH)D levels in the insufficiency range during wintertime. Elderly subjects have mean 25(OH)D levels in the insufficiency range throughout the year. In institutionalized subjects 25(OH)D levels are often in the deficiency range. There is now general agreement that a low vitamin D status is involved in the pathogenesis of osteoporosis. Moreover, vitamin D insufficiency can lead to a disturbed muscle function. Epidemiological data also indicate a low vitamin D status in tuberculosis, rheumatoid arthritis, multiple sclerosis, inflammatory bowel diseases, hypertension, and specific types of cancer. Some intervention trials have demonstrated that supplementation with vitamin D or its metabolites is able: (i) to reduce blood pressure in hypertensive patients; (ii) to improve blood glucose levels in diabetics; (iii) to improve symptoms of rheumatoid arthritis and multiple sclerosis. The oral dose necessary to achieve adequate serum 25(OH)D levels is probably much higher than the current recommendations of 5-15 microg/d.

Serum 25-hydroxyvitamin D levels and the prevalence of peripheral arterial disease: results from NHANES 2001 to 2004. Melamed ML, Muntner P, Michos ED, Uribarri J, Weber C, Sharma J, Raggi P. Arterioscler Thromb Vasc Biol. 2008 Jun;28(6):1179-85. Epub 2008 Apr 16. PMID: 18417640 doi: 10.1161/ATVBAHA.108.165886 Conclusions- Low serum 25(OH)D levels are associated with a higher prevalence of PAD. Several mechanisms have been invoked in the literature to support a potential antiatherosclerotic activity of vitamin D. Prospective cohort and mechanistic studies should be designed to confirm this association. Vitamin D is an inhibitor of the renin-angiotensin system and has antiinflammatory and anticoagulant properties. Among 4839 NHANES 2001 to 2004 participants, low 25(OH)D levels were associated with a higher prevalence of PAD, after multivariate adjustment. To confirm this association, longitudinal cohort and mechanistic studies are needed.

Low vitamin d levels predict stroke in patients referred to coronary angiography. Pilz S, Dobnig H, Fischer JE, Wellnitz B, Seelhorst U, Boehm BO, März W. Stroke. 2008 Sep;39(9):2611-3. Epub 2008 Jul 17. PMID: 18635847 doi: 10.1161/STROKEAHA.107.513655 Conclusions- Low levels of 25(OH)D and 1,25(OH)2D are independently predictive for fatal strokes, suggesting that vitamin D supplementation is a promising approach in the prevention of strokes.

Independent association of low serum 25-hydroxyvitamin d and 1,25-dihydroxyvitamin d levels with all-cause and cardiovascular mortality. Dobnig H, Pilz S, Scharnagl H, Renner W, Seelhorst U, Wellnitz B, Kinkeldei J, Boehm BO, Weihrauch G, Maerz W. Arch Intern Med. 2008 Jun 23;168(12):1340-9. PMID: 18574092 Conclusions Low 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D levels are independently associated with all-cause and cardiovascular mortality. A causal relationship has yet to be proved by intervention trials using vitamin D.

Vitamin D deficiency and risk of cardiovascular disease. Wang TJ, Pencina MJ, Booth SL, Jacques PF, Ingelsson E, Lanier K, Benjamin EJ, D'Agostino RB, Wolf M, Vasan RS. Circulation. 2008 Jan 29;117(4):503-11. Epub 2008 Jan 7. PMID: 18180395 doi: 10.1161/CIRCULATIONAHA.107.706127 Conclusions- Vitamin D deficiency is associated with incident cardiovascular disease. Further clinical and experimental studies may be warranted to determine whether correction of vitamin D deficiency could contribute to the prevention of cardiovascular disease.

Evolution and function of vitamin D. Holick MF. Recent Results Cancer Res. 2003;164:3-28. Review. PMID: 12899511

25-hydroxyvitamin D and risk of myocardial infarction in men: a prospective study. Giovannucci E, Liu Y, Hollis BW, Rimm EB. Arch Intern Med. 2008 Jun 9;168(11):1174-80. PMID: 18541825 Conclusion Low levels of 25(OH)D are associated with higher risk of myocardial infarction in a graded manner, even after controlling for factors known to be associated with coronary artery disease.

Optimal vitamin D status attenuates the age-associated increase in systolic blood pressure in white Americans: results from the third National Health and Nutrition Examination Survey. Judd SE, Nanes MS, Ziegler TR, Wilson PW, Tangpricha V. Am J Clin Nutr. 2008 Jan;87(1):136-41. PMID: 18175747 Conclusions: SBP is inversely associated with serum vitamin D concentrations in nonhypertensive white persons in the United States. This observation provides a rationale for studies on the potential effects of vitamin D supplementation as a method to reduce SBP in persons at risk of hypertension.

Sunlight and vitamin D: both good for cardiovascular health. Holick MF. J Gen Intern Med. 2002 Sep;17(9):733-5. PMID: 12220371 doi: 10.1046/j.1525-1497.2002.20731.x.

Serum 25-hydroxyvitamin D3 concentrations and carotid artery intima-media thickness among type 2 diabetic patients. Targher G, Bertolini L, Padovani R, Zenari L, Scala L, Cigolini M, Arcaro G. Clin Endocrinol (Oxf). 2006 Nov;65(5):593-7. PMID: 17054459 DOI: 10.1111/j.1365-2265.2006.02633.x CONCLUSIONS: Hypovitaminosis D is highly prevalent in type 2 diabetic adults and is strongly and independently associated with increased carotid IMT. Further investigation into whether vitamin D may play a role in the prevention of atherosclerosis appears to be warranted. In conclusion, our results show that type 2 diabetic adults have significant reductions in serum 25(OH)D concentrations (vs matched controls) that predict preclinical atherosclerosis, independent of classical risk factors, renal function tests, inflammatory markers, use of medications and presence of the metabolic syndrome. These findings suggest the need for ongoing evaluation of the possible protective role of vitamin D3 supplementation in the development of atherosclerosis.

Vitamin D and disease prevention with special reference to cardiovascular disease. Zittermann A. Prog Biophys Mol Biol. 2006 Sep;92(1):39-48. Epub 2006 Feb 28. Review. PMID: 1660034

Prevalence and Associations of 25-Hydroxyvitamin D Deficiency in US Children: NHANES 2001-2004. Kumar J, Muntner P, Kaskel FJ, Hailpern SM, Melamed ML. Pediatrics. 2009 Aug 3. [Epub ahead of print] PMID: 19661054 CONCLUSIONS: 25(OH)D deficiency is common in the general US pediatric population and is associated with adverse cardiovascular risks.

1,25(OH)2 vitamin d inhibits foam cell formation and suppresses macrophage cholesterol uptake in patients with type 2 diabetes mellitus. Oh J, Weng S, Felton SK, Bhandare S, Riek A, Butler B, Proctor BM, Petty M, Chen Z, Schechtman KB, Bernal-Mizrachi L, Bernal-Mizrachi C. Circulation. 2009 Aug 25;120(8):687-98. Epub 2009 Aug 10. PMID: 19667238 doi: 10.1161/CIRCULATIONAHA.109.856070 Conclusion- These results identify reduced vitamin D receptor signaling as a potential mechanism underlying increased foam cell formation and accelerated cardiovascular disease in diabetic subjects.