**6. Observational data**

Several large‐scale observational studies have been completed over the past decades.

The NHANES III national cohort registry analyzed 15,088 subjects using a cross‐sectional design and found that. 25(OH)D levels were inversely associated with hypertension, diabetes mellitus, hypertriglyceridemia, and obesity [5, 35].

Similar conclusions were obtained in the prospective analysis of 41,504 patients from The Intermountain Heart Collaborative Study Group, in which serum 25(OH)D levels <30 ng/ml were associated with highly significant increases in the prevalence of diabetes, hypertension, hyperlipidemia, and peripheral vascular disease. Serum 25(OH)D levels were also highly associated with coronary artery disease, myocardial infarction, heart failure, stroke, and incident death [18].

In the Health Professionals Follow‐up Study, men deficient in 25(OH)D (<15 ng/ml) were at increased risk for myocardial infarction compared with those considered to be vitamin D sufficient (>30 ng/ml) RR, 2.09; 95% CI, 1.24–3.54; *P* = 0.02 for trend) even after risk factor adjustment [50]. It could be hypothesized that this increased risk may be explained by a pro‐ inflammatory state induced by vitamin D deficiency.

In contrast, other prospective studies have had discordant results. The MIDSPAN family study followed 2338 subjects prospectively for a median of 14.4 years. Plasma levels of 25(OH)D <15 ng/ml were not associated with a risk of cardiovascular diseases, but did relate to all‐cause mortality. There was an association between 25(OH)D levels and incidence of type 2 diabetes, but there was no evidence that vitamin D supplementation improved outcomes in these subjects [51]. Follow‐up of 3135 patients from the Osteoporotic Fractures in Men (MrOS) study and included in the MrOS Sleep Study failed to establish a significant association between circulating 25(OH) vitamin D and risk of CVD events [52].

Aside from actual CVD events and mortality, other endpoints using surrogate markers have been studied. In a prospective Austrian cohort of 3258 patients referred for coronary angiog‐ raphy and followed up for 7.7 years, low 25(OH)D levels correlated inversely with markers of inflammation (C‐reactive protein and interleukin‐6), oxidative burden (serum phospholipid and glutathione), and cell adhesion (vascular cell adhesion molecule‐1 and intercellular adhesion molecule‐1) [6].

A myriad of observational data relates low vitamin D status to an increased prevalence of hypertension. In the Third National Health and Nutrition Examination Survey (NHANES‐III), systolic blood pressure (BP) had a significant inverse correlation to 25(OH)D levels. Mean systolic and diastolic BP were 3.0 and 1.6 mm Hg (*P* < 0.05) lower for participants in the highest quintile compared with the lowest, after adjusting for potential confounders. Age‐adjusted systolic BP was significantly lower in individuals with vitamin D sufficiency [5].

A prospective analysis among 1211 non‐hypertensive US men found an inverse relationship between vitamin D levels and development of hypertension over a 15‐year follow‐up period. VDR BsmI and FokI polymorphisms were also associated with increased risk of hypertension [53].

Additionally, a more recent study involving 746 patients failed to demonstrate significant relationship between serum vitamin D levels and the severity and extent of coronary artery disease [54].

Aside from the link between developing hypertension and low vitamin D levels, the Framing‐ ham Offspring Study suggested that low serum vitamin D levels may augment the risk associated with existing hypertension to dramatically raise the risk of future cardiovascular events [55].
