Vitamin D and Cerebrovascular Disease.

EDITORIAL COMMENTARY

Vitamin D [25-Hydroxyvitamin D (25(OH) D)], is a secosteroid provitamin obtained by dermal synthesis following exposure to sun and through oral consumption from food and supplements. Though initially related to bone and mineral homeostasis, a diversified range of physiological roles of 25(OH) D has been documented over the years. Concurrently, a vast array of >100 human diseases have been linked to low circulating concentrations of 25(OH) D.[1] The intriguing but worrisome estimates of more than a half of global population with inadequate vitamin D status, suggest a vast potential for vitamin D-based interventions targeted at the prevention, and management of these diseases.[2]

In the present point-of-view article, the authors have presented an epidemiological as well as clinical perspective on the incidence, severity, and rehabilitation of stroke caused by vitamin D deficiency.[3] Although a decline in stroke mortality has been documented recently in developed nations because of the implementation of strict guidelines on risk factor management like hypertension,[45] the global burden of stroke continues to rise due to an increase in the developing countries.[4] The authors have presented an overall view on the association of vitamin D status with stroke risk; most of the evidence discussed is derived from reported observational prospective studies.[3] The authors have also given a run-through over the status of intervention studies; however, a few important reports could be included. To this end, we would like to refer to the recently published, randomized, placebo-controlled, VITAL trial, that reported no decrease in the incidence of cardiovascular events including stroke in the elderly, when the use of vitamin D supplements and marine omega-3 fatty acids were compared with placebo, during a mean follow-up of 5.3 years.[6] The trial concluded that the beneficial influences of vitamin D supplementation on stroke risk could only be limited to severely vitamin D deficient individuals. The finding raises concerns on the implementation of vitamin D supplementation for the prevention of stroke. Similarly, the recent findings from a prospective, population-based study (n = 9680) from Rotterdam[7] showed low circulating vitamin D in prevalent stroke but only severe vitamin D deficiency was linked to incident stroke. The study concluded with a view that lower vitamin D levels might not lead to higher stroke risk, but rather could be an outcome of stroke.[7]

Given the inconsistent findings with a lack of reports on large sample sizes, the authors have indicated the limitations in inferring the causal association of vitamin D deficiency with stroke and have advocated that this should be explored in further studies.[3] Authors have also opined that a plausible causal relationship between vitamin D deficiency and risk of stroke cannot be excluded based on a recently published Mendelian randomized study.[38] In the referred study on 116,655 individuals, observational but not genetic low 25(OH)D concentration was linked to ischemic stroke; however, a causal relationship could be established between vitamin D deficiency and hypertension through the Mendelian randomization approach.[8] An interesting mechanistic and epidemiological intersection lies between vitamin D levels, risk of stroke, and hypertension, one of the most prevalent pathophysiological risk factors for stroke.[9] In a case–control study from China, the joint occurrence of vitamin D deficiency with hypertension was found to increase the probability of developing small vessel stroke by 5.6-fold [OR = 5.609 (95% CI 2.006–15.683)].[10] Similarly, in our cross-sectional evaluation in an Asian Indian population, the presence of hypertension was found to aggravate the risk of ischemic stroke associated with low vitamin D levels. We observed a distinct association between reduced circulating 25(OH)D and risk of ischemic stroke in hypertensives (OR = 13.54, 95% CI = 1.94–94.43) when compared to lack of association in non-hypertensives, (P = 0.04).[11] The synergistic influence of severely deficient vitamin D status along with hypertension on an aggravated stroke risk needs meticulous assessment in a prospective and interventional manner to answer the issue of combined treatment of low vitamin D levels and/or hypertension to prevent stroke and reduce the severity of its outcomes.