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6 Vitamin D: Cardiovascular Function and Disease 125

a possible explanation for the inconsistent results reported during this period. Thus,
by the end of this period, it was still not possible to conclude whether vitamin D in
physiological doses was beneficial, harmful or irrelevant to CV health.

6.4 2000s: Increasing Evidence of a Beneficial
Cardiovascular Effect

The number of publications on vitamin D and CV disease has rapidly increased in
the first decade of the new millennium (Fig. 6.1). This new research has been influ-
enced by reports from large epidemiological studies showing inverse associations
between vitamin D and CV disease, initially from cohorts of hemodialysis patients,
but in 2008 from general population cohorts. Coinciding with these new epidemio-
logical findings has been the publications from patient and animal studies providing
new insights into possible mechanisms linking vitamin D and CV disease.

6.4.1 Studies in Hemodialysis Patients

CV disease is the main cause of death in developed countries. Interest in the benefi-
cial effects from vitamin D against CV disease was stimulated by a landmark pub-
lication by US researchers showing that a cohort of hemodialysis patients on
paricalcitol had a 16% reduction in all-cause mortality compared with those on
calcitriol [122]. The authors of this report restricted their comparisons to those on
either form of activated vitamin D by excluding patients not on any form of vitamin
D to avoid confounding by indication. Thus, the possibility remained that the
reduced mortality in those taking paricalcitol was an artifact caused by increased
mortality in those taking calcitriol. However, the latter possibility was dispelled by
a Japanese cohort study showing decreased CV mortality in dialysis patients on
alfacalcidol compared to no vitamin D, the adjusted hazard ratio being 0.38 (95%
CI: 0.25, 0.58) of CV mortality over 5 years [123].
This finding was confirmed by a further cohort study of 51,000 US hemodialysis
patients, which found a CV disease incidence rate of 7.6 per 100 person-years in
the vitamin D-treated group (mainly calcitriol or paricalcitol) compared with 14.6
per 100 person-years in the nonvitamin D group (p < 0.001), with the relative reduc-
tion in all-cause mortality being 20% [124]. Of interest in relation to the possible
protective mechanisms associated with vitamin D (see Sect. 6.4.4), this study also
reported a significant reduction in mortality from an infectious disease among the
vitamin D-treated group compared with the untreated (1.1 vs 2.8 deaths per 100
person-years, p < 0.0001). Similar findings were observed in a recent cohort study
of hemodialysis patients from six Latin American countries, with patients given
oral active vitamin D having reduced mortality (of about 50%) from all-causes,