The Role of the Intraplaque Vitamin D System in Atherogenesis

Table 1

Observational studies investigating the relationship between vitamin D and carotid intima-media thickness.

Author	Year	Study design; (sample size)	Country; (ethnicity); Age	Correlation; (lower range of 25(OH)D)	Findings
Briese et al. [41]	2006	Case-control; (40 ESRD patients and 40 matched healthy controls)	Germany; (Caucasian); Mean 23.6 years	No; (linear correlation)	There was no difference in CCA-IMT between the two groups. This study failed to correlate 25(OH)D and cIMT.
Targher et al. [38]	2006	Case-control; (390 TDM2 patients and 390 healthy controls)	Italy; (Caucasian); 50–65 years	Yes; (<37.5 nmol/L)	Low 25(OH)D level independently predicted CCA-IMT (𝑃<0.001).
Kraśniak et al. [40]	2007	Cross-sectional; (73 patients in haemodialysis)	Poland; (Caucasian); 25–75 years	Yes; (linear correlation)	The study showed a linear inverse correlation between 25(OH)D and CCA-IMT at univariate analysis (𝑃<0.01).
Michos et al. [46]	2009	Cross-sectional; (650 Amish people)	U.S.; (Caucasian); Stratified	No; (I quartile < 18.1 nmol/L)	The study failed to detect an association between 25(OH)D and cIMT.
Pilz et al. [47]	2009	Prospective observational; (614 subjects from the Hoorn study)	Netherlands; (Caucasian); Mean 68.5 years	No; (not provided)	This post hoc analysis failed to detect an association between 25(OH)D and cIMT.
Reis et al. [48]	2009	Cross-sectional; (654 older adults from Rancho Bernardo Study)	U.S.; (Caucasian); 55–96 years	Yes; (I quartile < 32.0 nmol/L)	In this study, 25(OH)D was associated with geometric mean internal cIMT (𝑃 for trend = 0.02) but not CCA-IMT. Instead 1,25(OH)2D or PTH did not correlate with IMT.
Hajas et al. [58]	2011	Cross-sectional; (125 females MCTD patients)	Hungary; (Caucasian); Mean 53.6	Yes; (linear correlation)	The study reported a significant linear inverse association between 25(OH)D and cIMT (𝑃<0.001).
Richart et al. [49]	2011	Cross-sectional; (542 females from FLEMENGHO study)	Belgium; (Caucasian); Stratified	No; (linear correlation)	cIMT was associated with PTH/25(OH)D ratio (𝑃<0.01), not with 25(OH)D alone.
Choi et al. [43]	2011	Cross-sectional; (139 HIV-infected subjects)	U.S.; (Caucasian and African Americans); Mean 45 years	Yes (<37.5 nmol/L)	At adjusted analysis, 25(OH)D insufficiency was associated with higher mean cIMT levels (𝑃=0.02).
Ross et al. [44]	2011	Case-control; (149 HIV-infected subjects)	U.S.; (Caucasian and African Americans); Not provided	Yes; (not provided)	At adjusted analysis, 25(OH)D insufficiency increased risk of CCA-IMT (OR 10.62 (CI 95% 1.37–82.34); 𝑃<0.01).
Pacifico et al. [59]	2011	Cross-sectional; (452 children and adolescent)	Italy; (Caucasian); Stratified	No; (I tertile < 42.5 nmol/L)	This post hoc analysis failed to detect an association between 25(OH)D and cIMT.
Carrelli et al. [50]	2011	Cross-sectional; (203 subjects from the Northern Manhattan study)	U.S.; (Caucasian and African Americans); 50–93 years	Yes; (linear correlation)	Multiple regression analysis showed an independent inverse correlation of 25(OH)D with cIMT (𝑃=0.05) as well as total plaque thickness (𝑃=0.03).
Shikuma et al. [45]	2012	Cross-sectional; (1003 HIV-infected subjects from the HAHC-CVD)	U.S.; (Caucasian and other races); Mean 52 years	No; (I tertile < 25 nmol/L)	This cohort did not show any correlation between 25(OH)D and cIMT.
Lim et al. [51]	2012	Cross-sectional; (921 subjects from the KLoSHA)	Korea; (Asian); Mean 76	No; (<37.5 nmol/L)	This study failed to prove a correlation between 25(OH)D and cIMT.
Liu et al. [39]	2012	Cross-sectional; (300 TDM2 patients)	China; (Asian); Not provided	Yes (<26.17 nmol/L)	Lower 25(OH)D levels inversely correlated with cIMT (𝑃 for trend < 0.05) also at multivariate analysis (𝑃<0.01). Similar findings were observed comparing patients with and without carotid atherosclerosis (𝑃<0.01).
Knox et al. [52]	2012	Cross-sectional; (625 healthy subjects from pSoBid study)	UK; (not provided); 35–64	No; (linear correlation)	There was no evidence of an association of increasing 25(OH)D with risk of plaque presence or cIMT in the whole group in univariate or adjusted models.
Zang et al. [42]	2012	Cross-sectional; (151 patients with diabetic nephropathy)	China; (Asian); Not provided	No; (<37.5 nmol/L)	This study failed to prove a correlation between 25(OH)D and cIMT.
Oz et al. [60]	2013	Cross-sectional; (222 patients undergoing coronary angiography)	Turkey; (Turkish); Stratified	Yes; (<75 nmol/L)	The vitamin D deficient group showed an independent and inverse correlation with cIMT (𝑃<0.001)
Blondon et al. [53]	2013	Cross-sectional and longitudinal; (3251 subjects from the Multi-Ethnic Study of Atherosclerosis)	US; (Caucasian, African Americans, Asian, Hispanic); Mean 60 years	No; (<50 nmol/L)	At multivariate analysis 25(OH)D failed to correlate with cIMT both in cross-sectional and in longitudinal analysis.
Kiani et al. [61]	2013	Longitudinal observational; (154 patients from the LAPS)	US; (Caucasian, African Americans, and others); Stratified; Mean 46 years	No; (<52.5 nmol/L)	After 2 years of follow-up, this study failed to prove a correlation between 25(OH)D and cIMT.
Sypniewska et al. [62]	2014	Cross-sectional; (98 hypertensive patients)	Poland; (Caucasian); 42–58 years	Yes; (<52.5 nmol/L)	In this cohort, 25(OH)D was inversely correlated with cIMT (𝑃<0.02).
Deleskog et al. [37]	2013	Longitudinal observational; (3430 subjects with high CV risk)	Europe; (not provided); Mean 64 years	No; (<25 nmol/L)	25(OH)D correlated with CV risk factors but not with cIMT progression after 30 months follow-up.

ESRD: end-stage renal disease; CCA-IMT: common carotid artery intima-media thickness; cIMT: carotid intima-media thickness; TDM2: type 2 diabetes mellitus; PTH: parathyroid hormone; MCTD: mixed connective tissue disease; FLEMENGHO: Flemish Study on Environment, Genes and Health Outcomes; HIV: human immunodeficiency virus; OR: odds ratio; CI: confidence of interval; HAHC-CVD: Hawaii aging with HIV-cardiovascular; KLoSHA: Korean Longitudinal Study on Health and Aging; pSoBid: psychological, social and biological determinants of ill health; LAPS: Lupus Atherosclerosis Prevention Study; and CV: cardiovascular.