Vitamin D Levels on the Risk of Myocardial Infarction and Mortality
The Effects of Vitamin D Supplementation
and 25-Hydroxyvitamin D Levels on the
Risk of Myocardial Infarction and Mortality
There is substantial evidence implicating vitamin D (Vit-D) levels in the pathogenesis of cardiovascular risk factors such as diabetes, hypertension, hyperlipidemia, chronic kidney disease, and obesity. Furthermore, experimental studies suggest that Vitamin D may participate in pathways associated with atherosclerosis by influencing cellular growth, oxidative stress, membrane transport, cell adhesion, and gene regulation.
Direct effects of Vitamin D on cardiomyocytes and vascular endothelial cells
were reported via Vitamin D receptors.
The Endocrine Society defines 25-hydroxyvitamin D ([25-OH]D) levels ≤20 ng/mL as a deficiency, levels 21-29 ng/mL as insufficiency, and levels ≥30 ng/mL as optimal. However, data regarding the association of the (25-OH)D levels and Vitamin D supplementation with myocardial infarction (MI) and mortality remains controversial.
Several meta-analyses of epidemiological studies suggested that Vitamin D deficiency is associated with an increased risk of MI and cardiovascular mortality. One meta-analysis suggested that there is generally a linear, inverse association between circulating (25-OH)D levels and the risk of cardiovascular disease. A Cochrane meta-analysis showed that Vitamin D treatment significantly reduced mortality in subgroups of patients with a pretreatment level below 20 ng/mL. However, in several randomized controlled trials, supplementation of Vitamin D did not result in lower cardiovascular events and mortality.
It is important to note that the majority of these randomized controlled trials had included patients who already had optimal baseline (25-OH)D levels, with most patients in these trials having pretreatment (25-OH)D levels above 25 to 30 ng/mL. Additionally, in the majority of these clinical trials, post-treatment follow-up of (25-OH)D was not measured to account for effective supplementation and had a short-term follow-up. Even in the VITAL (vitamin D and omega-3 trial) and the VIDA (vitamin D assessment) trials, only a small subset of the study population (6.3% and 8.6%, respectively) had a repeat measurement of post-treatment (25-OH)D level performed. It is also worth noting that in several studies, the association between Vitamin D and the risk of MI was apparent only after long-term follow-up. Additionally, there is limited data available comparing the outcome of MI and mortality with respect to the levels of (25-OH)D achieved and maintained after Vitamin D supplementation.
To address this gap in knowledge, we conducted a large retrospective analysis with long-term follow-up in patients with low baseline Vitamin D level who had at least 2 separate measurements of (25-OH)D levels to confirm their status and to measure the effect of Vit-D supplementation on (25-OH)D levels. The goal of our study was to examine the effects of Vit-D treatment (VDT) and lack of VDT on all-cause mortality and MI in Vitamin D deficient patients without prior history of MI in relation to 3 different references levels of (25-OH)D as defined by the Endocrine Society.
The current study examined the effects of nontreatment and treatment in Vit-D–deficient patients without a prior history of MI in relation to 3 different reference levels of (25-OH)D. Based on the long-term follow-up, our study found that the patients with post-treatment (25-OH)D levels at or above 30 ng/mL had a lower incidence of MI and all-cause mortality. These results suggest that targeting 25(OH)D levels above 30 ng/mL might improve prognosis in the primary prevention setting among individuals with Vitamin D deficiency.
Objective: The aim of the study was to examine the effects of the vitamin D (Vit-D) treatment and nontreatment on Vit-D–deficient patients without a prior history of myocardial infarction (MI).
Materials and Methods: This was a retrospective, observational, nested case-control study of patients (N = 20 025) with low 25-hydroxyvitamin D ([25-OH]D) levels (<20 ng/mL) who received care at the Veterans Health Administration from 1999 to 2018. Patients were divided into 3 groups: Group A (untreated, levels ≤20 ng/mL), Group B (treated, levels 21-29 ng/mL), and Group C (treated, levels ≥30 ng/mL). The risk of MI and all-cause mortality were compared utilizing propensity score–weighted Cox proportional hazard models.
Results: Among the cohort of 20 025 patients, the risk of MI was significantly lower in Group C than in Group B (hazard ratio [HR] 0.65, 95% CI 0.49-0.85, P = .002) and Group A (HR 0.73, 95% CI 0.55-0.96), P = .02). There was no difference in the risk of MI between Group B and Group A (HR 1.14, 95% CI 0.91-1.42, P = 0.24). Compared with Group A, both Group B (HR 0.59, 95% CI 0.54-0.63, P < .001) and Group C (HR 0.61, 95% CI 0.56-0.67, P < .001) had significantly lower all-cause mortality. There was no difference in all-cause mortality between Group B and Group C (HR 0.99, 95% CI 0.89-1.09, P = .78).
Conclusions: In patients with Vit-D deficiency and no prior history of MI, treatment to the (25-OH)D level of >20 ng/mL and >30 ng/mL was associated with a significantly lower risk of all-cause mortality. The lower risk of MI was observed only in individuals maintaining (25-OH)D levels ≥30 ng/mL.
The pathophysiological mechanism for our findings remains speculative. The predominant cause of mortality in patients with (25-OH)D levels ≤20 ng/mL is likely multifactorial, and possibly related to the pleiotropic effect of Vitamin D on immunity, cardiovascular health, and metabolic abnormalities associated with its deficiency. Additionally, our data suggest that in Vitamin D deficient patients, post-treatment (25-OH)D levels of 21-29 ng/dL may provide inadequate protection against MI and to derive significant MI benefit post-treatment (25-OH)D levels should be >30 ng/dL.
Experimental studies have demonstrated that Vitamin D inhibits the transformation of macrophages to foam cells, increases cholesterol efflux in macrophages, improves endothelial nitric oxide formation, promotes vascular repair, and decreases thrombogenicity as well as inflammation. All these mechanisms may play a role in providing a protective effect against the atherothrombotic process such as MI.
Results from our current study suggest in patients with Vitamin D deficiency and no prior history of MI, treatment to the (25-OH)D level of >20 ng/mL was associated with a significantly lower risk of all-cause mortality. Our study also highlights that in this population reduction in the risk of MI was observed only with the increase in the (25-OH)D levels to ≥30 ng/mL. In the future, adequately powered, prospective, well-designed trials with a long-term follow-up will be needed to reach a conclusive agreement regarding the effect of Vitamin D supplementation, and post supplement (25-OH)D target levels on MI risk.
Journal of the Endocrine Society, 2021, Vol. 5, No. 10, 1–11 Clinical Research Article https://doi.org/10.1210/jendso/bvab124