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Does Vitamin D Have a Role in Reducing the Risk of Peripheral Artery Disease?–Reply–I

      Drs Mascitelli, Goldstein, and Grant highlight several important points regarding the potential role of vitamin D in the pathogenesis and treatment of peripheral artery disease (PAD).
      Large observational studies have thus far linked low levels of vitamin D to various cardiovascular diseases.
      • Giovannucci E
      • Liu Y
      • Hollis BW
      • Rimm EB
      25-hydroxyvitamin D and risk of myocardial infarction in men: a prospective study.
      • Reis JP
      • von Muhlen D
      • Michos ED
      • et al.
      Serum vitamin D, parathyroid hormone levels, and carotid atherosclerosis.
      • Giovannucci E
      Vitamin D and cardiovascular disease.
      A case-control study of 18,225 men showed that those with low levels of plasma 25-hydroxyvitamin D were at increased risk of myocardial infarction compared with those with normal levels. This risk of myocardial infarction increased as the level of vitamin D decreased, even after adjusting for traditional cardiovascular risk factors.
      • Giovannucci E
      • Liu Y
      • Hollis BW
      • Rimm EB
      25-hydroxyvitamin D and risk of myocardial infarction in men: a prospective study.
      Pilz et al
      • Pilz S
      • Marz W
      • Wellnitz B
      • et al.
      Association of vitamin D deficiency with heart failure and sudden cardiac death in a large cross-sectional study of patients referred for coronary angiography.
      followed up 3299 patients for 7.7 years and found that vitamin D deficiency was associated with heart failure and sudden cardiac death. Furthermore, vitamin D deficiency has been linked to hypertension,
      • Scragg R
      • Sowers M
      • Bell C
      Serum 25-hydroxyvitamin D, ethnicity, and blood pressure in the Third National Health and Nutrition Examination Survey.
      stroke,
      • Pilz S
      • Dobnig H
      • Fischer JE
      • et al.
      Low vitamin D levels predict stroke in patients referred to coronary angiography.
      PAD,
      • Melamed ML
      • Muntner P
      • Michos ED
      • et al.
      Serum 25-hydroxyvitamin D levels and the prevalence of peripheral arterial disease: results from NHANES 2001 to 2004.
      and other cardiometabolic factors.
      • Reis JP
      • von Muhlen D
      • Miller III, ER
      • Michos ED
      • Appel LJ
      Vitamin D status and cardiometabolic risk factors in the United States adolescent population.
      Low 25-hydroxyvitamin D levels have been associated with an increased all-cause and cardiovascular mortality in older community-dwelling adults.
      • Semba RD
      • Houston DK
      • Bandinelli S
      • et al.
      Relationship of 25-hydroxyvitamin D with all-cause and cardiovascular disease mortality in older community-dwelling adults.
      Melamed et al
      • Melamed ML
      • Muntner P
      • Michos ED
      • et al.
      Serum 25-hydroxyvitamin D levels and the prevalence of peripheral arterial disease: results from NHANES 2001 to 2004.
      analyzed data from a national survey (National Health and Nutrition Examination Survey 2001 to 2004) that obtained vitamin D levels in 4839 adults and showed that those with vitamin D levels in the highest quartile had a significantly lower prevalence of PAD than those with vitamin D levels in the lowest quartile (3.7% vs 8.1%). After adjustment for confounding variables, this remained statistically significant.
      Does vitamin D have an important pathogenetic role in cardiovascular diseases, or is the level of vitamin D merely a consequence of the disease? For example, individuals with heart failure, stroke, or PAD have a poor quality of life and markedly reduced functionality, often limiting outdoor activities that may result in low vitamin D levels. Furthermore, there is an inverse relationship between low vitamin D levels and activation of the renin-angiotensin-aldosterone cascade, thus elevating blood pressure and potentially increasing cardiovascular events.
      • Giovannucci E
      Vitamin D and cardiovascular disease.
      Is vitamin D the cause of these perturbations in cardiovascular health, or are these associations noncausal and confounded by other factors?
      The letter from Mascitelli et al highlights the potential role of novel risk factors for PAD and should provoke more insightful research in the future. Although the information provided by recent observational studies clearly shows that low vitamin D levels are associated with adverse cardiovascular outcomes, the small number of randomized trials published to date does not confirm these observations.
      • Trivedi DP
      • Doll R
      • Khaw KT
      Effect of four monthly oral vitamin D3 (cholecalciferol) supplementation on fractures and mortality in men and women living in the community: randomised double blind controlled trial.
      • Hsia J
      • Heiss G
      • Ren H
      • et al.
      Calcium/vitamin D supplementation and cardiovascular events.
      In a study of 2686 men and women aged 65 to 85 years, participants were randomized to receive 100,000 IU oral vitamin D3 (cholecalciferol) supplementation or matching placebo every 4 months for 5 years.
      • Trivedi DP
      • Doll R
      • Khaw KT
      Effect of four monthly oral vitamin D3 (cholecalciferol) supplementation on fractures and mortality in men and women living in the community: randomised double blind controlled trial.
      Even though fractures were reduced in men and women, there was no difference in all-cause mortality between the group that received vitamin D and the group that received placebo. In the Women's Health Initiative, 36,282 postmenopausal women aged 50 to 79 years were randomized to receive calcium (1000 mg/d) and vitamin D3 (400 IU/d) or placebo.
      • Hsia J
      • Heiss G
      • Ren H
      • et al.
      Calcium/vitamin D supplementation and cardiovascular events.
      During 7 years of follow-up, there was no difference in the rate of myocardial infarction, coronary heart disease, death, or stroke in the calcium/vitamin D3 group compared with the group receiving placebo.
      Therefore, we do not support the use of vitamin D supplementation for either the prevention or the treatment of PAD or other cardiovascular diseases until large-scale randomized, controlled studies demonstrate efficacy.

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