Children with low serum vitamin-D levels in childhood appear to have an increased likelihood of developing subclinical atherosclerosis in adulthood independent of conventional cardiovascular risk factors, the results of a Finnish study indicate.
The results show that low 25-hydroxy (25-OH) vitamin-D levels in childhood are associated with increased carotid intima-media thickness (IMT) almost 30 years later, particularly in females.
"From a clinical perspective, our findings suggest that suboptimal vitamin-D levels in childhood should be considered a possible risk factor for adult cardiovascular disease, although the therapeutic implications are unknown," the researchers, led by Markus Juonala, MD, PhD, from the University of Turku, Finland, write.
The work was published online February 10 in the Journal of Clinical Endocrinology and Metabolism.
Asked to discuss the findings, Daniel D Bikle, MD, PhD, from the University of California, San Francisco School of Medicine, observed that the study has some strengths and some weaknesses.
"I'm not a cardiologist, but we're not getting the hard end point here. This is 'subclinical' atherosclerosis....There are no strokes here, there are no myocardial infarctions," he explained to Medscape Medical News.
Surprising Gender Difference Unearthed
Explaining what prompted the study, Dr Juonala told Medscape Medical News: "There were earlier studies among adults with somewhat-controversial results concerning vitamin-D levels and cardiovascular health. We wanted therefore to explore the associations between childhood vitamin-D levels and an early marker of atherosclerosis, carotid IMT."
The researchers examined data from the Cardiovascular Risk in Young Finns Study on 2148 individuals recruited in 1980, when aged 3 to 18 years. Serum samples were taken at baseline and analyzed for 25-OH vitamin-D levels using radioimmunoassay in 2010. Serum samples were also taken at the 27-year follow-up, in 2007, and analyzed in 2008. Participants were then categorized into quartiles or quintiles of 25-OH vitamin-D levels.
Cardiovascular risk factors were assessed in childhood and adulthood, and ultrasound IMT measurements were performed on the left carotid artery. These were analyzed both as a continuous and dichotomous IMT variable, the latter categorizing patients as high risk if they were in the 90th percentile of thickness or they had a carotid plaque.
The results indicate that girls had significantly lower childhood 25-OH vitamin-D concentrations than boys, at 50.0 mmol/L vs 53.3 mmol/L (P < .0001). There was also a significant correlation between baseline and follow-up 25-OH vitamin-D concentrations in both males and females (P < .0001 for both).
Analysis revealed that continuous childhood 25-OH vitamin-D levels were significantly associated with adult carotid IMT levels, after researchers took into account age, sex, and childhood risk factors, in females (P = .03) but not in males (P = .88).
Furthermore, children in the lowest quartile for 25-OH vitamin-D levels (< 40 mmol/L) had a significantly increased likelihood of high-risk IMT in adulthood, after adjustment for age, sex, and either childhood or adult risk factors, at odds ratios of 1.70 (P = .0007) and 1.80 (P = .0004), respectively.
These associations were found to be significant in both males and females (P < .05 in all cases). The team also found that using quintiles of 25-OH vitamin-D levels yielded similar results as those seen when using quartiles.
"The strength of association was as expected, but the gender difference was somewhat surprising and will need further research in different cohorts and settings," Dr Juonala commented. "One possible reason for gender difference is that girls had overall lower vitamin-D levels," he added.
But while the association between early 25-OH vitamin-D levels in childhood and subclinical atherosclerosis in adulthood is certainly interesting, it is not possible to make any further inferences at this stage, he noted.
"Unfortunately, this is an observational study, and we cannot say for sure whether vitamin D is a causal factor. Even though we were able to take into account several other factors, there are still unexplored…factors."
Dr Juonala continued: "I think the major implication would be an increased awareness of vitamin-D levels in children, as more evidence is needed for detailed clinical recommendations."
Strengths and Weaknesses
Dr Bikle said the main plus of the study is that the researchers measured 25-OH vitamin-D levels when the participants were young and then looked at carotid IMT almost 3 decades later.
"I consider that a strength, because probably vitamin-D deficiency has very long-term consequences, which are not so easily found when you are measuring the 25-OH vitamin-D levels somewhere around the time when you are also making the outcome measurements, in this case the IMT," Dr Bikle said.
"That's supported by the fact that, when they measured the 25-hydroxy vitamin-D levels at the same time as they did the IMT measurements, they didn't see these associations.
"So, the strength is that they have a 'prospective trial,' although one uses that term very loosely, and this is the major weakness of it," he explained
He added that all studies of this nature are, in reality, association studies. "It doesn't really prove anything. It says that there's a possibility, and I think that the authors, with all due respect, are cognizant of these weaknesses."
As an example, Dr Bikle observed that the results indicate that there is no "easy" linear association between the cut points for 25-OH vitamin D and high-risk IMT determinants. "It does not prove that vitamin-D deficiency in childhood, per se, in my opinion, causes any atherosclerosis," he said.
Jury Still Out on vitamin-D Deficiency
Dr Bikle said that to demonstrate that vitamin-D deficiency is associated with atherosclerosis would take a "truly prospective" trial lasting 20 to 30 years. "Nobody's…going to do that," he said. "It's hard enough getting a grant for 5 years, let alone 30."
He commented that, while he is a "believer" in vitamin D, he shares the skepticism expressed over the strength of association between vitamin-D levels and its putative effects.
For example, the Institute of Medicine Dietary Reference Intakes for Calcium and Vitamin D states that there is insufficient evidence to say that vitamin-D levels are associated with anything other than falls and fracture risk, which Dr Bikle described as a "fair statement."
Citing also the Endocrine Society's Scientific Statement on the Nonskeletal Effects of Vitamin D, which Dr Bikle coauthored, he continued: "On the other hand, I think the association data with respect to low vitamin D being a cause of a variety of adverse events, including all-cause mortality, cardiovascular disease, and certain cancers, are pretty strong too.
"In my practice, I think that it's better to be safe than sorry, because the upper limit of the 25-hydroxy vitamin-D levels that I try to achieve in my patients is very much considered safe by all parties involved."
He concluded: "We are kind of stuck with the fact that it's very likely that we won't know for sure that it's vitamin D, as opposed to a whole variety of other factors that vitamin-D deficiency might be associated with; you know, poor nutrition, lack of sunlight, and obesity for sure."
The study was financially supported by the Academy of Finland, the Social Insurance Institution of Finland, the Turku University Foundation, Paulo Foundation, Paavo Nurmi Foundation, Juho Vainio Foundation, Sigrid Juselius Foundation, Maud Kuistila Foundation, research funds from the Kuopio, Turku, and Tampere University Hospitals, the Finnish Foundation of Cardiovascular Research, the Finnish Medical Foundation, the Orion-Farmos Research Foundation, and the Finnish Cultural Foundation. The authors have reported no relevant financial relationships .
J Clin Endocrinol Metab. Published online February 10, 2015. Abstract
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Cite this: Childhood Vitamin D Levels Linked to Later Atherosclerosis - Medscape - Feb 18, 2015.