Potential pathophysiological role for the vitamin D deficiency in essential hypertension

Table 1 Cross-sectional studies evaluating vitamin D blood pressure

Ref.	Year	Study design(sample size)	Country (ethnicity)Age	Correlation (lower reference range of 25(OH) vitamin D)	Findings
Snijder et al[67]	2007	Cross-sectional from the LASA (1205 subjects more than 65 yr old)	Netherlands (caucasian) men and women ≥ 65 yr	No (I quartile: < 25 nmol/L)	25(OH) vitamin D was not associated with systolic or diastolic BP or prevalence of hypertension. Instead, PTH correlated with both BP and hypertension incidence
Martins et al[95]	2007	Cross-sectional from the 1988-1994 NHANES (15088 subjects)	United States (Caucasian and African Americans and other) men and women age stratified	Yes (I quartile: < 52.5 nmol/L)	Adjusted inter-quartile analysis showed an increased prevalence of hypertension in in the lower quartile of 25(OH) vitamin D (OR = 1.30, 95%CI; 1.13-1.49; P < 0.05)
Scragg et al[96]	2007	Cross-sectional from the 1988-1994 NHANES (12644 subjects not treated with anti-hypertensive drugs)	United States (Caucasian and African Americans and other) men and women age stratified	Yes (I quintile: < 40 nmol/L)	Adjusted inter-quintile analysis of 25(OH) vitamin D showed significant inverse correlation with both systolic (P < 0.01) and diastolic (P < 0.05) BP. This association was stronger in more than 50 years old and black people
Judd et al[97]	2008	Cross-sectional from the 1988-1992 NHANES (7699 non-hypertensive subjects)	United States (White and black people ) men and women age stratified	Yes (Vitamin D deficiency defined as < 50 nmol/L)	Lower 25(OH) vitamin D concentrations were associated with a higher blood pressure category in white people (P < 0.01) but after adjustment for age the association was no longer significant
Hintzpeter et al[98]	2008	Cross-sectional from GNHIES (4030 adults)	Germany (Caucasian) men and women 18-79 yr	Yes (Vitamin D deficiency defined as < 12 nmol/L[99])	According to 25(OH) vitamin D levels, in multivariate analysis there was a relationship between 25(OH) vitamin D and hypertension bot in men (OR = 0.97, 95%CI: 0.94-0.99; P < 0.05) and in women (OR 0.96, 95%CI: 0.93-0.99; P < 0.05)
Hypponen et al[100]	2008	Cross-sectional from 1958 British birth cohort (6810 subjects)	United Kingdom (Caucasian) men and women 45-47 yr	Yes (I tertile: < 45 nmol/L)	The lower 25(OH) vitamin D tertile was associated with hypertension (OR 0.72, 95%CI: 0.61-0.86; P < 0.01)
Reis et al[101]	2009	Cross-sectional from the 2001-2004 NHANES (3577 non-pregnant adolescents without diagnosed diabetes)	United States (Caucasian and African Americans and other) male and female adolescent 12-19 yr	Yes (I quartile: < 37.5 nmol/L)	25(OH) vitamin D was inversely associated with systolic BP (P < 0.05) also in the adjusted odds ratio for the interquartile comparison (OR = 2.36, 95%CI: 1.33-4.19; P < 0.05)
Pasco et al[102]	2009	Cross-sectional (861 subjects)	Australia (Caucasian) women: 20-92 yr	Yes (I tertile 25(OH)D: < 30 nmol/L)	In this cohort there was a significant inter-tertile difference in mean BP (P < 0.001) as well as in anti-hypertensive medication use (P < 0.01)
Almirall et al[103]	2010	Cross-sectional (237 subjects more than 64 years old)	Spain (Caucasian) men and women 64-93 yr	Yes (cut-off for vitamin D deficiency: < 62.5 nmol/L)	A significant negative association was observed between serum 25(OH) vitamin D levels and both systolic (P < 0.05) and diastolic BP (P < 0.05) also in multivariate analysis
Jorde et al[104]	2010	Cross-sectional from the Tromsø Study (4125 subjects not treated with anti-hypertensive drugs)	Norway (Caucasian) Men and women age stratified	Yes (I quartile: < 41.4 nmol/L)	At adjusted inter-quartile analysis serum 25(OH) vitamin D was inversely correlated with systolic BP (P < 0.01)
Kim et al[105]	2010	Cross-sectional (1330 subjects)	South Korea (Asian)	Yes (I quintile: < 29.7 nmol/L)	At adjusted inter-quintile analysis, both systolic and diastolic BP decreased linearly with increasing of 25(OH) vitamin D (quintile 1-5; P for trend < 0.01). Moreover, inter-quintile comparison of BP had OR of 0.42 (95%CI: 0.24-0.73; P < 0.05)
Zhao et al[106]	2010	Cross-sectional from the 2003-2006 NHANES (5414 subjects not assuming anti-hypertensive drugs)	Men and women < 40 yr United States (Hispanic, Caucasian and African Americans) men and women ≥ 20 yr	Yes (I quintile: < 37.5 nmol/L	Across 25(OH) vitamin D quintiles systolic and diastolic BP decreased linearly and inversely (P < 0.01). Moreover, the prevalence ratio for hypertension was lower in the highest quintile (OR = 0.82, 95%CI: 0.73-0.91; P < 0.05)
Fraser et al[107]	2010	Cross-sectional from the 2001-2006 NHANES (3958 subjects)	United States (Caucasian and African Americans and other) men and women ≥ 20 yr	Yes (linear correlation)	25(OH) vitamin D has an inverse linear correlation with systolic blood pressure in various adjusted models (P < 0.05)
Steinvil et al[108]	2011	Cross-sectional case-control study (34874 subjects of which 8387 hypertensive)	Israel men and women 38-72 yr	Yes (vitamin D deficiency defined as < 37.5 nmol/L)	The age-adjusted OR for hypertension among normal and deficient serum 25(OH) vitamin D was 1.19 (95%CI: 1.09-1.31; P < 0.01) in women, whereas in men there was not statistical difference
Burgaz et al[109]	2011	Cross-sectional from the ULSAM (833 adult men)	Sweden (Caucasian) Men 71 yr	Yes (vitamin D deficiency defined as < 37.5 nmol/L)	Adjusted logistic regression confirmed the association between 25(OH) vitamin D concentration < 37.5 nmol/L and hypertension (OR = 3.3, 95%CI: 1.0-11.0; P < 0.05)
Bhandari et al[110]	2011	Cross-sectional (2722 subjects of which 1415 hypertensive)	United States (Caucasian and African Americans and other) men and women mean age 58.5 yr	Yes (I quartile: < 37.5 nmol/L)	The prevalence rate of hypertension was inversely correlated with serum 25(OH) vitamin D. Inter-quartile comparison showed an adjusted OR of 2.70 (95%CI: 1.41-5.19; P < 0.05)
Pacifico et al[111]	2011	Cross-sectional case-control study (452 children and adolescent of which 304 over-weight/obese and 148 normal weight)	Italy (Caucasian) Male and female children	Yes (I tertile of 1,25(OH)2 vitamin D: < 42.5 nmol/L)	1,25(OH)2 vitamin D was inversely correlated with systolic BP both in the whole population (P < 0.01) and over-weight (P < 0.01) population as well as in control group (P < 0.01). Regardless of model for adjusted analysis, the OR for hypertension among tertile categories had a P value < 0.05.
Williams et al[112]	2011	Cross-sectional from 2003-2006 NHANES (5617 adolescent)	United States (Caucasian and African Americans and other) male and female children 12-19 yr	Yes (linear correlation)	In this cohort, 25(OH) vitamin D showed a linear inverse association with systolic BP in multivariate analysis (P < 0.01).
Forrest et al[113]	2011	Cross-sectional from 2005-2006 NHANES (4495 adults subjects of which 1482 hypertensive)	United States (Caucasian and African Americans and other) Men and women age stratified	Yes (vitamin D deficiency defined < 50 nmol/L[114])	Vitamin D deficiency independently correlated with prevalence of hypertension (P < 0.01).
He et al[70]	2011	Cross-sectional from 2003-2006 NHANES (7561 of which 1849 treated with anti-hypertensive drugs)	United States (Caucasian and African Americans and other) Men and women age stratified	No (I quintile: < 33 nmol/L)	25(OH) vitamin D was inversely associated with systolic BP. However, 25(OH) vitamin D lost its statistical significance in a multivariate analysis including PTH. Instead, PTH maintained a strong correlation with BP in multivariate analysis regardless of covariates.
Dorjgochoo et al[115]	2012	Cross-sectional study from two, population-based, prospective cohort studies (1460 subjects of which 547 hypertensive)	China (Asian) men and women 40-74 yr	Yes (lowers range defined by I quintile 23.5 nmol/L and cut-offs of 37.5 nmol/L[116] and 27.5 nmol/L[117])	Among men cohort, BP was inversely and significantly correlated with 25(OH) vitamin D (P < 0.05). Moreover, prevalence of hypertension was inversely associated with non-deficient status of vitamin D (adjusted OR = 0.29, 95%CI: 0.10-0.82; P < 0.05)
Sakamoto et al[118]	2013	Cross-sectional from the AHS-2 (568 subjects)	United States (equally matched Caucasian and African Americans) men and women 30-95 yr	Yes (vitamin D deficiency defined as < 50 nmol/L)	Regardless of adjusted analysis models, Caucasian people showed a linear inverse correlation between 25(OH) vitamin D and BP (P < 0.05). Also the comparison between vitamin D deficient and non-deficient showed statistical difference (P < 0.05).
Li et al[64]	2012	Cross-sectional (1420 subjects of which 487 hypertensive)	China (Asian) Men and women ≥ 65 yr	No (I quartile: < 42 nmol/L)	Serum 25(OH) vitamin D levels were not associated with risk of hypertension in single and multiple regression models. Similarly, PTH is not independently associated with BP or risk of hypertension
Caro et al[119]	2012	Cross-sectional (219 subjects of which 115 hypertensive)	Puerto Rico (Hispanic) Men and women 21-50 yr	No (cut-off used to define non optimal: 75 nmol/L)	Vitamin D status was not found to be associated with BP
Chan et al[72]	2012	Cross-sectional (939 men aged 65 yr and older)	China (Asian) men ≥ 65 yr (age strafied)	No (I quartile: < 63 nmol/L)	Vitamin D status was not found to be associated with BP. Instead, PTH was directly and independently associated with BP also in multivariate analysis.
Parikh et al[120]	2012	Cross-sectional (701 adolescents)	United States (Caucasian and African Americans) Male and female 14-18 yr	Yes (I tertile: < 54.8 nmol/L)	Serum 25(OH) vitamin D has a linear inverse correlation with both systolic (P < 0.05) and diastolic (P < 0.01) BP. However, in the adjusted analysis only the relationship with systolic BP remained significant.
Sabanayagam et al[121]	2012	Cross-sectional from NHANES III (9215 subjects of which 3712 with pre-hypertension)	United States (Caucasian and African Americans and other) men and women age stratified	Yes (I quartile: < 44.25 nmol/L)	In this cohort the systolic BP are inversely correlated with the vitamin D status (P < 0.05) and lower values of 25(OH) vitamin D were associated with increase prevalence of pre-hypertension (adjusted OR = 1.48, 95%CI: 1.16-1.90; P value for trend < 0.01).
van Ballegooijen et al[122]	2012	Cross-sectional from the Hoorn study (256 subjects)	The Netherlands (Caucasian) men and women 50-75 yr	Yes (I quartile: < 60.8 nmol/L)	In this cohort there was an inverse correlation between 25(OH) vitamin D and both systolic and diastolic BP (P value for trend < 0.01 for both)
Skaaby et al[123]	2012	Cross-sectional 4330 subjects)	Denmark (Caucasian) men and women 30-60 yr	No (I quartile: < 33 nmol/L)	Mean 25(OH) vitamin D levels did not differed between hypertensive and normotensive subjects. There was not increased prevalence of hypertension in vitamin D deficient subjects
Kruger et al[124]	2013	Cross-sectional form the PURE study (291 African women)	All over the world countries (African) women > 47 yr	Yes (vitamin D deficiency defined as < 30 nmol/L[125])	Both systolic and diastolic BP correlated linearly and inversely with serum 25(OH) vitamin D level (P < 0.05 for both). However, only systolic BP maintain statistical significance in multivariate analysis (P < 0.05).
Mateus-Hamdan et al[73]	2013	Cross-sectional (284 geriatric patients of which 106 hypertensive)	France men and women mean age 85 ± 6 yr	No (linear correlation)	Means PTH but not 25(OH) vitamin D levels are significant different in hypertensive compared to normotensive patients.
Ke et al[126]	2013	Cross-sectional from the ATBC (2271 subjects of which 1430 hypertensive)	Finland (Caucasian) men and women 50-69 yr	Yes (I quartile: < 25 nmol/L)	Serum 25(OH) vitamin D level has a significant and inverse association with systolic BP (P < 0.05), also if stratified in groups. Moreover, the lower group was associated with increased prevalence of hypertension in multivariate analysis (P value for trend < 0.05).

LASA: Longitudinal aging study amsterdam; 25(OH)D: Cholecalciferol; BP: Blood pressure; PTH: Parathyroid hormone; NHANES III: Third United States national health and nutrition examination survey; OR: Odds ratio; GNHIES: German national health Interview and examination survey; ULSAM: Uppsala Longitudinal study of adult men; AHS-2: Adventist health study-2; PURE study: Prospective urban and rural epidemiology study; ATBC: Alpha-tocopherol and beta-carotene study.