Atherosclerosis 237 (2014) 734e738

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Measuring coronary artery calcification: Is serum vitamin D relevant? Rehan Malik a, 1, Ehimen C. Aneni a, *, 1, Lara Roberson a, Oluseye Ogunmoroti a, Shozab S. Ali a, b, Sameer Shaharyar a, c, Adnan Younus a, Omar Jamal a, Muhammad A. Aziz a, Seth S. Martin d, Michael J. Blaha d, Theodore Feldman a, Arthur S. Agatston a, Emir Veledar a, e, Khurram Nasir a, d, e, f a

Center for Prevention and Wellness Research, Baptist Health Medical Group, Miami, FL, USA University of Manchester School of Medicine, Manchester, United Kingdom Aventura Hospital and Medical Center, Aventura, Florida d Ciccarone Center for the Prevention of Heart Disease, Johns Hopkins University, Baltimore, MD, USA e Robert Stempel College of Public Health, Florida International University, Miami, FL, USA f Herbert Wertheim College of Medicine, Florida International University, Miami, FL, USA b c

a r t i c l e i n f o

a b s t r a c t

Article history: Received 26 August 2014 Received in revised form 24 October 2014 Accepted 27 October 2014 Available online 28 October 2014

Objectives: To synthesize evidence of the association between low vitamin D levels and subclinical coronary atherosclerosis measured by coronary artery calcium (CAC). Methods: A systematic MEDLINE search was conducted for relevant published literature. Ten studies (7 cross-sectional, 3 longitudinal) met the inclusion criteria. Results: Three of 6 studies showed association with CAC prevalence (CAC >0 or >10). Four of 8 studies found an association with CAC severity. One of two studies reported an association with CAC progression, while the only study that assessed CAC incidence did not find a significant relationship. Several of the studies had small sample sizes, many did not adjust for confounders and the cutoff for low vitamin D was inconsistent. Conclusion: There is insufficient evidence to support a consistent association between low vitamin D levels and CAC. Further high-quality studies are needed to examine serum 25-OH vitamin D in relation to subclinical coronary atherosclerosis. © 2014 Published by Elsevier Ireland Ltd.

Keywords: Serum vitamin D Coronary artery calcification Atherosclerosis

1. Introduction Despite significant progress in primary prevention and treatment strategies, cardiovascular disease (CVD) mortality remains a major health burden. Recent statistics indicate that approximately 35% of the US population has at least one form of CVD. Coronary artery disease contributes to about half of all CVD related deaths [1]. Coronary atherosclerosis, often measured by coronary arterial calcium (CAC), is thought to play a major role in the development of symptomatic CVD. Several studies have linked CAC to CVD events and the absence of CAC is associated with low risk of incident clinical CVD and CVD mortality [2e4]. Although the link between vitamin D status and clinical CVD is not fully understood, it is thought that atherosclerosis plays a major role [5]. This assertion is supported by the studies that describe an

* Corresponding author. Center for Prevention and Wellness, Baptist Health South Florida, 1500 San Remo Ave., Suite 350, Miami, Fl, 33146, USA. E-mail address: [email protected] (E.C. Aneni). 1 Co-first authors. http://dx.doi.org/10.1016/j.atherosclerosis.2014.10.087 0021-9150/© 2014 Published by Elsevier Ireland Ltd.

association between low levels of vitamin D and atherosclerotic CVD events [5,6]. In light of this, recent studies have focused their efforts on the relationship between the most commonly measured metabolite of vitamin D, 25-hydroxy vitamin D (here on referred to as vitamin D), and measures of subclinical CVD such as CAC. Studies on the relationship between vitamin D and CAC have yielded very contrasting results, with some failing to show any relationships. With growing interest in this topic, there is increased need to sort out and synthesize the available evidence of the relationship between serum vitamin D levels and CAC.

2. Methods We performed a computerized MEDLINE search using the PubMed and OvidSP search engines with key words and MeSH terms such as “vitamin D”, “25-hydroxy vitamin D”, “atherosclerosis”, “cardiovascular diseases”, “CAC”, “coronary calci*”, “coronary artery calcium” or “agatston score”. We included all literature published before 01 January 2014. The search was limited to articles published in the English language. There were no country

R. Malik et al. / Atherosclerosis 237 (2014) 734e738

restrictions, and abstracts were reviewed for appropriateness by two authors (RM, ECA). To be included in the synthesis, studies had to be crosssectional, case-control or prospective in design and conducted in adult populations. Eligible studies clearly defined a threshold for low vitamin D, had a comparison vitamin D group and used CAC measures. We excluded studies of CVD events or populations with established CVD, including peripheral vascular disease. We also examined the references of all studies from the initial search for additional references. Reviewed studies were limited to those published in peer-reviewed journals (see Fig. 1). Full text review of the selected articles was conducted to confirm their inclusion. Extracted data on the studies, participant characteristics and results were entered into tables (see Table 1). The final data was collated and presented in the text.

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differences in the mean CAC between low and adequate vitamin D levels. Among those reporting no significance, 50% (2 of 4) had small sample sizes (80 and 154 participants respectively) [9,16]. 3.3. Vitamin D and high vs. low CAC Two studies compared high CAC groups to low CAC groups across vitamin D levels [14,15]. One compared prevalence of CAC>100 while the other had a cut-off of CAC >400. Both studies showed an association between low vitamin D and higher CAC, although the study with a cut-off of CAC >100 did not reach statistical significance after adjusting for confounding variables [15]. Taken together, a total of 4 studies (50%) found significant associations suggesting that vitamin D is associated with CAC severity while 4 did not. Therefore, there is inconclusive evidence of the association between vitamin and CAC severity.

3. Results 3.4. Vitamin D and CAC incidence A total of ten studies were included in this review; 3 were longitudinal, the others were cross-sectional in design. Essential features and findings of each of the studies are summarized in the table. 3.1. 25 OH vitamin D and CAC prevalence Six studies reported on CAC prevalence, defined here as CAC >0 or >10 [7e12]. Among these, 3 studies demonstrated significant association between vitamin D and CAC; only 2 controlled for confounders. One of the studies reporting a significant association, Shikuma et al., had modest elevated unadjusted risk (RR 1.02; p ¼ 0.04) and did not perform multivariable adjustment [8]. The three other studies with no association between vitamin D and CAC prevalence included studies conducted in a multi-ethnic population [7], among persons with type 1 diabetes [11] and in a population of persons with chronic kidney disease [9]. Two of these 3 studies [7,11] had adequate sample sizes. As such, the evidence of an association between low vitamin D levels and the presence of CAC is inconclusive. 3.2. Vitamin D and average CAC Six studies compared average CAC values across groups of vitamin D [9,11,13e16]. Among these, 2 reported significant

Fig. 1. Flow chart of studies found from literature search.

Only one study assessed low vitamin D levels and incident CAC [7]. This study, conducted in the Multi-Ethnic Study of Atherosclerosis (MESA) population, did not find any association between low vitamin D levels and incident CAC when vitamin D levels were treated as binary. However, when looking at vitamin D as a continuous variable, the incidence of coronary calcium was higher per 10 ng/ml reduction in vitamin D. Since this is the only study, there is not enough evidence of an association between vitamin D and incident CAC. 3.5. 25 OH vitamin D and CAC progression Two studies investigated low vitamin D levels and CAC progression, with contrasting results. One study found a significant association between their measure of low vitamin D and CAC progression (defined as change in square root transformed calcium volume scores  2.5) among persons who had no CAC at baseline (CAC ¼ 0) if they had a vitamin D receptor (VDR) M1T CC genotype but not in those with either the CT and TT genotypes. M1T is a common genetic variant of the VDR gene and has C and T alleles. The other study assessing CAC progression did not demonstrate any significant association. Therefore, there is inconclusive evidence of an association between vitamin D and CAC progression. 4. Discussion This systematic review found insufficient evidence to support a consistent association between vitamin D levels and the severity, incidence or progression of CAC. Multiple longitudinal studies have suggested an association between low levels of vitamin D and CVD events, such as myocardial infarction and stroke, but there have been concerns that this is a non-causal association [17e19]. These concerns are supported by the failure of vitamin D supplementation trials to show CVD risk reduction [20]. Despite the evidence linking low vitamin D levels to elevated vascular inflammation and endothelial dysfunction, both pathogenetic mechanisms of atherosclerosis, our review does not find conclusive evidence of an association between low vitamin D levels and CAC [21,22]. The exact mechanisms linking low vitamin D levels and CVD events remain unclear but findings from our review suggest that further high-quality research is needed to examine atherosclerosis development as a direct consequence of low vitamin D levels. Vitamin D is also associated with other CVD risk factors such as diabetes and hypertension [23,24] and worsening of these conditions may be the link between low vitamin D and CVD through non-atherosclerotic pathways.

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Table 1 Summary of studies examining coronary artery calcification and their association with serum vitamin D. First author, publication year type of study

Population description

Outcome ¼ CAC > 0/CAC > 10 de Boer, 2009 Longitudinal 1370 MESA study participants; Mean USA [7] Age ¼ 63 ± 10; Male ¼ 46%

Young, 2010 Longitudinal USA [12]

374 T1DM participants; Mean Age ¼ 40 ± 9; Male ¼ 46%

Shikuma, 2012 Longitudinal USA [8]

100 HIV infected participants; Median Age ¼ 52 (47e57); Male ¼ 86%

Pillar, 2012 Cross-sectional Brazil [9]

80 participants with CKD Mean Age ¼ 65 ± 13; male ¼ 40%

Lai, 2013 Cross-sectional USA [10]

846 HIV- infected AfricaneAmericans; Median Age (IQR) ¼ 46 (41e51) Male ¼ 63%

Sachs, 2013 Cross-sectional USA [11]

1081 T1DM Participants with Mean Age ¼ 32 ± 3; Male ¼ 53%

Outcome ¼ CAC ≥ 100 Lim, 2012 Cross-sectional Korea [15]

Outcome ¼ CAC > 400 Joergensen, 2011 Crosssectional Denmark [14]

Results

Comments

Adjusted RR (95%CI) for CAC > 0 comparing vitamin D < 15 ng/ml to vitamin D  15 ng/ ml ¼ 0.99 (0.88e1.11)

Adjusted for age, gender, race/ethnicity, site, season, measurement batch, physical activity, BMI, smoking, diabetes, BP, CRP, total cholesterol, HDL cholesterol, and triglycerides *Adjusted for BMI, HDL-c, LDL-c, triglycerides **Adjusted for above variables plus AER, vitamin d intake, and calcium intake 90 CAC measurements were available for analysis.

Minimally Adjusted OR (95%CI)* for CAC > 0 comparing vitamin D < 20 ng/ml to 30 ng/ ml ¼ 2.4 (1.1e5.3) Fully Adjusted OR** ¼ 2.2 (0.8e5.8) Non-adjusted RR (95% CI) for CAC >0. Vitamin D 10e30 ng/ml vs. 30 ng/ml RR ¼ 1.02 (CI ¼ NR); p ¼ 0.04 Ordered logistic regression (CAC categories 0, 1e99, 100e400, >400) Unadjusted OR ¼ 1.03 (CI ¼ NR); p ¼ 0.23 Frequency of CAC  10 Overall ¼ 57 (71%); vitamin D 17.2 ng/ml ¼ 29 (73%); p ¼ 0.80. Adjusted OR (95%CI) for CAC > 0 Ref ¼ vitamin D < 10 ng/ml vitamin D 10e20 ng/ml OR ¼ 0.53 (0.33e0.85) vitamin D 20e30 ng/ml OR ¼ 0.40 (0.24e0.68) vitamin D >30 ng/ml ¼ 0.61 (0.36e1.05). Vitamin D 10 ng/ml OR ¼ 1.98 (1.31 e3.00) Adjusted OR (95%CI) for CAC>0 Comparing vitamin D < 50 ng/ml vs. vitamin D  75 ng/ml OR ¼ 0.7 (0.47e1.05)

Adjusted for age, sex, family history, smoking, years of smoking, systolic BP, total cholesterol, LDL and HDL cholesterol, TG, Framingham risk score, cocaine use and years of cocaine use, years of ART initiation, exposure to NRTIs, PIs, exposure to any ART.

Adjusted for scanner type, age, diabetes duration, sex, race, BMI, AER, DCCT assignment, eGFR, solar irradiation of DCCT clinic site

921 men and women; Mean Age ¼ 76 ± 9; Male ¼ 44%

Frequency of CAC > 100 across vitamin D groups  Men (N ¼ 405) 30 ng/ml  15e29.9 ng/ml OR ¼ 3.31 (0.82e5.87);  30 at baseline  Among persons with CAC ¼ 0 at baseline

*Defined as change in square root transformed calcium volume scores (CVS) of 2.5 Adjusted for age, sex, hours of day light, BMI, HDL-cholesterol, LDL-cholesterol, triglycerides, AER, vitamin D intake and total calcium intake.

Outcome ¼ incident CAC de Boer, 2009 Longitudinal USA [7]

Outcome ¼ CAC progression Young, 2010 Longitudinal USA [12]

B VDR M1T (CC genotype only) OR ¼ 6.5 (1.1e40.2) B VDR M1T (CT or TT genotype) OR ¼ 1.6 (0.3e8.6)  Among persons with CAC > 0 at 3-year visit B VDR M1T (CC genotype only) OR ¼ 1.5 (0.2e9.4)

Kiani, 2013 Cross Sectional USA [16]

154 participants with SLE Mean Age ¼ 46 Male ¼ 8%

B VDR M1T (CT or TT genotype) OR ¼ 0.4 (0.1e1.5) Mean Change in CAC after 2 years FU across vitamin D groups  21e32 ng/ml ¼ 0.09; p ¼ 0.62;  32 ng/ml ¼ 0.19; p ¼ 0.25

No ORs reported.

Adjusted p value for difference in mean change ¼ p ¼ 0.10 Abbreviations: MESA Multi Ethnic Study of Atherosclerosis; BP blood pressure; BMI body mass index; CAC coronary artery calcium; CRP c-reactive protein; CVS calcium volume scores; T1DM Type 1 diabetes mellitus; T2DM Type 2 diabetes mellitus; HDL high density lipoprotein; iPTH intact parathyroid hormone; TG triglycerides; LDL low density lipoprotein; ART Antiretroviral therapy; NRTIs nucleoside reverse transcriptase inhibitor; PI protease inhibitor; HOMA-IR homeostasis model assessment-insulin resistance; Vitamin D 25 hydroxy vitamin D; VDR vitamin D receptor; VDR M1T vitamin D receptor M1T polymorphism CC genotype; VDR M1T (TT) vitamin D receptor M1T polymorphism TT genotype; VDR M1T (CT) vitamin D receptor M1T polymorphism CT genotype; SLE Systemic lupus erythematosus; AER Albumin excretion rate; OR odds ratio; RR relative risk; DCCT diabetes control and complication trial.

Our findings and conclusions may be impacted by the study's limitations. The significant heterogeneity in the definition of both low vitamin D and CAC measures precluded conducting a quantitative meta-analysis and has made stronger conclusions about the relationship between vitamin D and CAC difficult. Some studies included in this review had small sample sizes, which may have significantly affected their results. In addition, many of the studies did not adjust for possible confounders and several of the positive findings that may have been seen may indeed be due to confounding. Confounders we looked for in the studies include age, sex, race, renal function, BMI and other traditional CVD risk factors such as hypertension, diabetes, cigarette smoking, and serum lipids. Most of the studies were cross-sectional in nature leaving only a handful of studies assessing the temporal association between vitamin D levels and CAC. We also cannot rule out the possibility of publication bias. Our systematic review suggests that there is insufficient evidence of a relationship between coronary atherosclerosis as measured by CAC and low vitamin D levels, opening a discourse about other mechanisms of CVD in persons with low vitamin D. Considering the markedly high rates of vitamin D deficiency (42% overall and as high as 82% in AfricaneAmericans) [25], an association between vitamin D and atherosclerosis would have set in

motion further studies on vitamin D supplementation for the prevention atherosclerosis. Larger, well-conducted studies with longer follow-up periods are required to show a temporal association between vitamin D and CAC. References [1] A.S. Go, D. Mozaffarian, V.L. Roger, E.J. Benjamin, J.D. Berry, M.J. Blaha, S. Dai, E.S. Ford, C.S. Fox, S. Franco, et al., Heart disease and stroke statisticse2014 update: a report from the American Heart Association, Circulation 129 (3) (2014) e28ee292. [2] M. Blaha, M.J. Budoff, L.J. Shaw, F. Khosa, J.A. Rumberger, D. Berman, T. Callister, P. Raggi, R.S. Blumenthal, K. Nasir, Absence of coronary artery calcification and all-cause mortality, JACC Cardiovasc. Imaging 2 (6) (2009) 692e700. [3] R. Tota-Maharaj, M.J. Blaha, J.W. McEvoy, R.S. Blumenthal, E.D. Muse, M.J. Budoff, L.J. Shaw, D.S. Berman, J.S. Rana, J. Rumberger, et al., Coronary artery calcium for the prediction of mortality in young adults 75 years old, Eur. Heart J. 33 (23) (2012) 2955e2962. [4] M.J. Budoff, R.L. McClelland, K. Nasir, P. Greenland, R.A. Kronmal, G.T. Kondos, S. Shea, J.A. Lima, R.S. Blumenthal, Cardiovascular events with absent or minimal coronary calcification: the Multi-Ethnic Study of Atherosclerosis (MESA), Am. Heart J. 158 (4) (2009) 554e561. [5] E. Kassi, C. Adamopoulos, E.K. Basdra, A.G. Papavassiliou, Role of vitamin D in atherosclerosis, Circulation 128 (23) (2013) 2517e2531. [6] G.N. Thomas, B. o Hartaigh, J.A. Bosch, S. Pilz, A. Loerbroks, M.E. Kleber, J.E. Fischer, T.B. Grammer, B.O. Bohm, W. Marz, Vitamin D levels predict allcause and cardiovascular disease mortality in subjects with the metabolic

738

[7]

[8]

[9]

[10]

[11]

[12]

[13]

[14]

[15]

R. Malik et al. / Atherosclerosis 237 (2014) 734e738 syndrome: the Ludwigshafen Risk and Cardiovascular Health (LURIC) Study, Diabetes Care 35 (5) (2012) 1158e1164. I.H. de Boer, B. Kestenbaum, A.B. Shoben, E.D. Michos, M.J. Sarnak, D.S. Siscovick, 25-hydroxyvitamin D levels inversely associate with risk for developing coronary artery calcification, J. Am. Soc. Nephrol. JASN 20 (8) (2009) 1805e1812. C.M. Shikuma, T. Seto, C.Y. Liang, K. Bennett, V. DeGruttola, M. Gerschenson, J.H. Stein, M. Budoff, H.N. Hodis, J.A. Delaney, et al., Vitamin D levels and markers of arterial dysfunction in HIV, AIDS Res. Hum. Retrovir. 28 (8) (2012) 793e797. R. Pillar, M.G. GL, L.A. Rocha, L. Cuppari, A.B. Carvalho, S.A. Draibe, M.E. Canziani, Severe hypovitaminosis D in chronic kidney disease: association with blood pressure and coronary artery calcification, Hypertens. Res. Off. J. Jpn. Soc. Hypertens. 36 (5) (2013) 428e432. S. Lai, E.K. Fishman, G. Gerstenblith, J. Brinker, H. Tai, S. Chen, J. Li, W. Tong, B. Detrick, H. Lai, Vitamin D deficiency is associated with coronary artery calcification in cardiovascularly asymptomatic African Americans with HIV infection, Vasc. Health Risk Manag. 9 (2013) 493e500. M.C. Sachs, J.D. Brunzell, P.A. Cleary, A.N. Hoofnagle, J.M. Lachin, M.E. Molitch, M.W. Steffes, B. Zinman, I.H. de Boer, Circulating vitamin D metabolites and subclinical atherosclerosis in type 1 diabetes, Diabetes Care 36 (8) (2013) 2423e2429. K.A. Young, J.K. Snell-Bergeon, R.G. Naik, J.E. Hokanson, D. Tarullo, P.A. Gottlieb, S.K. Garg, M. Rewers, Vitamin D deficiency and coronary artery calcification in subjects with type 1 diabetes, Diabetes Care 34 (2) (2011) 454e458. E.D. Michos, E.A. Streeten, K.A. Ryan, E. Rampersaud, P.A. Peyser, L.F. Bielak, A.R. Shuldiner, B.D. Mitchell, W. Post, Serum 25-hydroxyvitamin d levels are not associated with subclinical vascular disease or C-reactive protein in the old order amish, Calcif. Tissue Int. 84 (3) (2009) 195e202. C. Joergensen, H. Reinhard, A. Schmedes, P.R. Hansen, N. Wiinberg, C.L. Petersen, K. Winther, H.H. Parving, P.K. Jacobsen, P. Rossing, Vitamin D levels and asymptomatic coronary artery disease in type 2 diabetic patients with elevated urinary albumin excretion rate, Diabetes Care 35 (1) (2012) 168e172. S. Lim, H. Shin, M.J. Kim, H.Y. Ahn, S.M. Kang, J.W. Yoon, S.H. Choi, K.W. Kim, J.H. Song, S.I. Choi, et al., Vitamin D inadequacy is associated with significant

[16]

[17]

[18] [19]

[20]

[21]

[22]

[23] [24]

[25]

coronary artery stenosis in a community-based elderly cohort: the Korean Longitudinal Study on Health and Aging, J. Clin. Endocrinol. Metab. 97 (1) (2012) 169e178. A.N. Kiani, H. Fang, L.S. Magder, M. Petri, Vitamin D deficiency does not predict progression of coronary artery calcium, carotid intima-media thickness or high-sensitivity C-reactive protein in systemic lupus erythematosus, Rheumatol. Oxf. Engl. 52 (11) (2013) 2071e2076. C.C. Welles, M.A. Whooley, S.A. Karumanchi, T. Hod, R. Thadhani, A.H. Berg, J.H. Ix, K.J. Mukamal, Vitamin D deficiency and cardiovascular events in patients with coronary heart disease: data from the Heart and Soul Study, Am. J. Epidemiol. 179 (11) (2014) 1279e1287. A. Zittermann, S.S. Schleithoff, R. Koerfer, Putting cardiovascular disease and vitamin D insufficiency into perspective, Br. J. Nutr. 94 (4) (2005) 483e492. R. Chowdhury, S. Kunutsor, A. Vitezova, C. Oliver-Williams, S. Chowdhury, J.C. Kiefte-de-Jong, H. Khan, C.P. Baena, D. Prabhakaran, M.B. Hoshen, et al., Vitamin D and risk of cause specific death: systematic review and metaanalysis of observational cohort and randomised intervention studies, BMJ Clin. Res. Ed. 348 (2014) g1903. J.A. Ford, G.S. MacLennan, A. Avenell, M. Bolland, A. Grey, M. Witham, Cardiovascular disease and vitamin D supplementation: trial analysis, systematic review, and meta-analysis, Am. J. Clin. Nutr. (2014). I. Al Mheid, R. Patel, J. Murrow, A. Morris, A. Rahman, L. Fike, N. Kavtaradze, I. Uphoff, C. Hooper, V. Tangpricha, et al., Vitamin D status is associated with arterial stiffness and vascular dysfunction in healthy humans, J. Am. Coll. Cardiol. 58 (2) (2011) 186e192. K.L. Jablonski, M. Chonchol, G.L. Pierce, A.E. Walker, D.R. Seals, 25-hydroxyvitamin D deficiency is associated with inflammation-linked vascular endothelial dysfunction in middle-aged and older adults, Hypertension 57 (1) (2011) 63e69. T.L. Van Belle, C. Gysemans, C. Mathieu, Vitamin D and diabetes: the odd couple, Trends Endocrinol. Metab. TEM 24 (11) (2013) 561e568. S.K. Kunutsor, T.A. Apekey, M. Steur, Vitamin D and risk of future hypertension: meta-analysis of 283,537 participants, Eur. J. Epidemiol. 28 (3) (2013) 205e221. K.Y. Forrest, W.L. Stuhldreher, Prevalence and correlates of vitamin D deficiency in US adults, Nutr. Res. NY 31 (1) (2011) 48e54.

Measuring coronary artery calcification: is serum vitamin D relevant?

To synthesize evidence of the association between low vitamin D levels and subclinical coronary atherosclerosis measured by coronary artery calcium (C...
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