tion through a mechanism independent of homocysteine lowering. Antoniades et al 3 independently demonstrated in human vessels that the beneficial effect of folic acid on endothelial dysfunction is explained by the interaction of folic acid and uncoupled endothelial nitric ox- ide synthase (eNOS); that is, folic acid increases the vascular availability of the essential eNOS cofactor tetrahydrobiop- terin and reduces eNOS-derived superox- ide generation. After myocardial infarc- tion, folic acid is beneficial to high-energy phosphate metabolism 4 and ventricular dysfunction. 4,5 Finally, the administration of folic acid improves endothelial progen- itor cell function. 6 In addition, an impor- tant distinction must be made between folic acid as a long-term, low-dose forti- fication or dietary supplement and as a short-term, high-dose treatment. Therefore, we would highly recom- mend that future studies and meta-analy- ses of vitamin B trials focus not only on their relation with homocysteine but also on dosage, duration of administration, study population, and the interaction of folic acid with the nitric oxide pathway and indicators for uncoupled eNOS such as asymmetrical dimethyl arginine. 7 Rinrada Kietadisorn, DVM, MSc Harald H. Schmidt, MD, PhD An L. Moens, MD, PhD Maastricht, The Netherlands 14 September 2010 1. Edgar RM III, Stephen J, Roberto P-B, Lydia AB, Lawrence JA, Eliseo G. Meta-analysis of folic acid supplementation trials on risk of cardiovascular disease and risk interaction with baseline homocysteine levels. Am J Car- diol 2010;106:517–527. 2. Moat SJ, Madhavan A, Taylor SY, Payne N, Allen RH, Stabler SP, Goodfellow J, McDow- ell IFW, Lewis MJ, Lang D. High- but not low-dose folic acid improves endothelial func- tion in coronary artery disease. Eur J Clin Invest 2006;36:850 – 859. 3. Antoniades C, Shirodaria C, Warrick N, Cai S, de Bono J, Lee J, Leeson P, Neubauer S, Ratna- tunga C, Pillai R, Refsum H, Channon KM. 5-Methyltetrahydrofolate rapidly improves endo- thelial function and decreases superoxide pro- duction in human vessels: effects on vascular tetrahydrobiopterin availability and endothelial nitric oxide synthase coupling. Circulation 2006; 114:1193–1201. 4. Moens AL, Champion HC, Claeys MJ, Tavazzi B, Kaminski PM, Wolin MS, Borgonjon DJ, Van Nassauw L, Haile A, Zviman M, Bedja D, Wuyts FL, Elsaesser RS, Cos P, Gabrielson KL, Lazzarino G, Paolocci N, Timmermans J-P, Vrints CJ, Kass DA. High-dose folic acid pre- treatment blunts cardiac dysfunction during isch- emia coupled to maintenance of high-energy phosphates and reduces postreperfusion injury. Circulation 2008;117:1810 –1819. 5. Qipshidze N, Tyagi N, Sen U, Givvimani S, Metreveli N, Lominadze D, Tyagi SC. Folic acid mitigated cardiac dysfunction by normal- izing the levels of tissue inhibitor of metallo- proteinase and homocysteine-metabolizing en- zymes post MI. Am J Physiol Heart Circ Physiol. In press. 6. van Oostrom O, de Kleijn D, Fledderus J, Pescatori M, Stubbs A, Tuinenburg A, Lim SK, Verhaar M. Folic acid supplementation normalizes the endothelial progenitor cell tran- scriptome of patients with type 1 diabetes: a case-control pilot study. Cardiovasc Diabetol 2009;8:47. 7. Pope AJ, Karuppiah K, Cardounel AJ. Role of the PRMT-DDAH-ADMA axis in the regula- tion of endothelial nitric oxide production. Pharmacol Res 2009;60:461– 465. doi:10.1016/j.amjcard.2010.09.001 Vitamin D Deficiency and Stroke: Time to Act! We read with great interest the excel- lent work by Anderson et al 1 who showed in 41,504 patients derived from a medical record database that a poor vitamin D status is associated with increased cardiovascular risk. We were impressed to see that low 25-hydroxyvitamin D (25[(OH)]D) levels are associated with previous and incident cerebrovascular accidents (CVAs). These findings extend previous observations from smaller studies and deserve partic- ular attention. 2–5 Evidence for low 25(OH)D levels in patients after stroke is of concern because common muscu- loskeletal complications of such pa- tients can be partly prevented by vita- min D intake, which significantly decreases falls and fractures and might have beneficial effects on neurologic and cognitive functions. 5,6 In this context it should be considered that limited mobility with decreased sunlight exposure and malnutrition are frequently observed in patients after stroke and contribute to vi- tamin D deficiency. 5 Apart from this, the strong association of low 25(OH)D lev- els with increased CVA incidence sug- gests that vitamin D therapy could be effective in preventing such events. This remains, however, to be proved in randomized controlled trials but accu- mulating evidence suggests that vitamin D supplementation might decrease ce- rebrovascular risk factors such as arte- rial hypertension. 5–7 Hence, in our cur- rent clinical practice we should consider the established and proposed multiple health benefits of vitamin D supplemen- tation. 5–7 Moreover, we should bear in mind that patients with previous CVAs are at particularly high risk of vitamin D deficiency itself and vitamin D deficien- cy-associated diseases including future CVAs. This patient group might there- fore particularly benefit from the pre- vention and treatment of a poor vitamin D status. Stefan Pilz, MD Andreas Tomaschitz, MD Winfried März, MD Graz, Austria 17 September 2010 1. Anderson JL, May HT, Horne BD, Bair TL, Hall NL, Carlquist JF, Lappe DL, Muhlestein JB, for the Intermountain Heart Collaborative (IHC) Study Group. Relation of vitamin D deficiency to cardiovascular risk factors, dis- eases status, and incident events in a general healthcare population. Am J Cardiol 2010;106: 963–968. 2. Kilkkinen A, Knekt P, Aro A, Rissanen H, Marniemi J, Heliövaara M, Impivaara O, Reu- nanen A. Vitamin D status and the risk of cardiovascular disease death. Am J Epidemiol 2009;170:1032–1039. 3. Drechsler C, Pilz S, Obermayer-Pietsch B, Verduijn M, Tomaschitz A, Krane V, Espe K, Dekker F, Brandenburg V, März W, Ritz E, Wanner C. Vitamin D deficiency is associated with sudden cardiac death, combined cardio- vascular events, and mortality in haemodialy- sis patients. Eur Heart J 2010;31:2253–2261. 4. Pilz S, Dobnig H, Fischer JE, Wellnitz B, Seel- horst U, Boehm BO, März W. Low vitamin D levels predict stroke in patients referred to coro- nary angiography. Stroke 2008;39:2611–2613. 5. Pilz S, Tomaschitz A, Drechsler C, Zittermann A, Dekker JM, März W. Vitamin D supple- mentation: a promising approach for the pre- vention and treatment of strokes. Curr Drug Targets 2010. [Epub ahead of print]. 6. Souberbielle JC, Body JJ, Lappe JM, Plebani M, Shoenfeld Y, Wang TJ, Bischoff-Ferrari HA, Cavalier E, Ebeling PR, Fardellone P, Gandini S, Gruson D, Guerin AP, Heicken- dorff L, Hollis BW, Ish-Shalom S, Jean G, von Landenberg P, Largura A, Olsson T, Pierrot- Deseilligny C, Pilz S, Tincani A, Valcour A, Zittermann A. Vitamin D and musculoskeletal health, cardiovascular disease, autoimmunity and cancer: recommendations for clinical prac- tice. Autoimmun Rev 2010;9:709 –715. 7. Reddy Vanga S, Good M, Howard PA, Vacek JL. Role of vitamin D in cardiovascular health. Am J Cardiol 2010;106:798 – 805. doi:10.1016/j.amjcard.2010.09.021 Erratum for Diaz VA et al. “Effect of healthy lifestyle behaviors on the association between leukocyte telomere length and coronary artery calcium” Am J Cardiol 2010;106: 659 – 663 Author Nilesh J. Samani was errone- ously listed as Nilesh J. Samanii. doi:10.1016/j.amjcard.2010.09.004 1674 The American Journal of Cardiology (www.ajconline.org)