CORRESPONDENCE: LETTER TO THE EDITOR
Reply
James H. O'Keefe, MD*,
John H. Lee, MD,
David S.H. Bell, MB and
Michael F. Holick, MD, PhD
* University of Missouri–Kansas City, Mid America Heart Institute, 4330 Wornall Road, Suite 2000, Kansas City, Missouri 64111-3217 (Email: jhokeefe{at}cc-pc.com).
We thank Dr. Mozaffarian and Drs. Pilz and Tomaschitz for their interest in our recent paper (1).
We agree with Dr. Mozafarrian that many of the prevalent health problems afflicting modernized societies result from dietary and lifestyle factors that are at odds with the evolutionary milieu for which we remain genetically adapted. Mounting worldwide deficiencies of fresh vegetables and fruits, outdoor exercise, omega-3 fatty acids, and vitamin D are all rooted in this fundamental displacement from our natural outdoor environment to an indoor sedentary lifestyle with a synthetic, highly processed, calorie-dense, nutritionally barren diet (2). The intuitive solution is to simulate that natural human diet and lifestyle to the extent that this is possible and practically achievable (3). Notwithstanding, many individuals may need daily supplements of vitamin D and omega-3 fats.
Dr. Mozafarrian questions whether the apparent cardiovascular (CV) benefits associated with higher vitamin D levels might be confounded by outdoor physical and social activities that will concomitantly increase vitamin D levels and reduce CV risk. To be sure, exercise confers powerful CV protection, and some evidence suggests that physical activity performed outside may be more beneficial than indoor exercise (4). Indeed, vitamin D produced in response to sun exposure maintains serum 25-hydroxyvitamin D [25(OH)D] levels longer than orally ingested vitamin D (5). Yet studies indicate that vitamin D synthesis in response to sunlight is highly variable depending on geographic location and season and on skin pigmentation. Even in locales with abundant sun exposure, such as Hawaii and southern Arizona, over 50% of inhabitants have been documented to be vitamin-D deficient (6,7). Moreover, excessive sunlight exposure in the times and locales characterized by intense ultraviolet radiation can predispose to skin cancers and premature skin aging, especially for individuals not genetically adapted (darker skin pigmentation) for equatorial climates. Thus, logical and effective strategies for maintaining normal vitamin D levels include safe sun exposure (15 to 20 min of daily unprotected sunlight exposure of arms and legs 3 times per week in the spring, summer, and fall), and oral vitamin D supplementation. The definitions of deficient, normal, and ideal vitamin D levels remain controversial. A target level for 25(OH)D of 30 to 60 ng/ml is safe and reasonable based on current data. Most studies indicate that upward of 50% of Americans have vitamin D 25(OH)D levels below 30 ng/ml, which can predispose to many CV problems, including statin-related myalgias (8).
The safety and efficacy of vitamin D supplementation for improving CV health will need to be established with large randomized controlled clinical trials. Generally, nutritional supplements, when tested in large randomized controlled trials, have not improved clinical outcomes. However, 2 notable exceptions exist: omega-3 and vitamin D. It is likely not coincidental that these same 2 essential nutrients are the ones most likely to be deficient among the American population (3,9). The quantity and quality of supportive randomized trial data for omega-3 exceeds that for vitamin D. Even so, the randomized controlled vitamin D trials performed to date have shown reductions in total mortality (10), fractures (11), and falls (12) when daily doses of  800 IU vitamin D were used.
Drs. Pilz and Tomaschitz highlight the growing body of evidence indicating that vitamin D deficiency adversely affects myocardial function and structure. This almost certainly contributes to the apparent CV toxicity of vitamin D deficiency.
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References
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1. 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;52:1949-1956.[Abstract/Free Full Text]2. O'Keefe Jr. JH, Cordain L. Cardiovascular disease resulting from a diet and lifestyle at odds with our Paleolithic genome: how to become a 21st-century hunter-gatherer Mayo Clin Proc 2004;79:101-108.[Abstract/Free Full Text] 3. O'Keefe JH, Gheewala NM, O'Keefe JO. Dietary strategies for improving post-prandial glucose, lipids, inflammation, and cardiovascular health J Am Coll Cardiol 2008;51:249-255.[Abstract/Free Full Text] 4. Peplonska B, Lissowska J, Hartman TJ, et al. Adulthood lifetime physical activity and breast cancer Epidemiology 2008;19:226-236.[CrossRef][Web of Science][Medline] 5. Holick MF. Vitamin D and sunlight: strategies for cancer prevention and other health benefits Clin J Am Soc Nephrol 2008;3:1548-1554.[Abstract/Free Full Text] 6. Jacobs ET, Alberts DS, Foote JA, et al. Vitamin D insufficiency in southern Arizona Am J Clin Nutr 2008;87:608-613.[Abstract/Free Full Text] 7. Binkley N, Novotny R, Krueger D, et al. Low vitamin D status despite abundant sun exposure J Clin Endocrinol Metab 2007;92:2130-2135.[Abstract/Free Full Text] 8. Duell PB, Connor WE. Vitamin D deficiency is associated with myalgias in hyperlipidemic subjects taking statins (abstr) Circulation 2008;118(Suppl):S470. 9. Block RC, Harris WS, Reid KJ, Sands SA, Spertus JA. EPA and DHA in blood cell membranes from acute coronary syndrome patients and controls Atherosclerosis 2008;197:821-828.[CrossRef][Web of Science][Medline] 10. Autier P, Gandini S. Vitamin D supplementation and total mortality: a meta-analysis of randomized controlled trials Arch Intern Med 2007;167:1730-1737.[Abstract/Free Full Text] 11. Bischoff-Ferrari HA, Willett WC, Wong JB, Giovannucci E, Dietrich T, Dawson-Hughes B. Fracture prevention with vitamin D supplementation: a meta-analysis of randomized controlled trials JAMA 2005;293:2257-2264.[Abstract/Free Full Text] 12. Broe KE, Chen TC, Weinberg J, Bischoff-Ferrari HA, Holick MF, Kiel DP. A higher dose of vitamin D reduces the risk of falls in nursing home residents: a randomized, multiple-dose study J Am Geriatr Soc 2007;55:234-239.[CrossRef][Web of Science][Medline]
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