In the current study, both high and low levels of 25(OH)D were positively associated with increased risks of severe AAC, and a U-shaped dose-response relationship (inflection point: 45.8ng/mL and 146ng/mL) was indicated, which was independent of several potential covariates, including age, gender, race, education level, marital, hypertension, diabetes, hypercholesterolemia, smoking and BMI. Further stratified analysis and subgroup analysis showed that the relationship of serum 25-hydroxyvitamin D levels and AAC severity in those subgroups was in accordance with that in the general population.
Vascular calcification is a complex process, which is featured by gradual accumulation of inflammatory cells, fatty deposits and calcium in the ILAW (intimal layer of arterial walls), and arterial calcification is characterized by calcium deposits in the medial or ILAW . The abdominal aorta is prone to atherosclerosis and calcification , and it is reported that the prevalence of AAC increases with age, ranging from 60% in individuals aged 65–69 to 96% in those aged 85 and above. At present, AAC is a marker of subclinical atherosclerosis and a predictor of subsequent vascular-associated morbidity and mortality , which is associated with the extent and severity of coronary artery disease , stroke and heart failure . Because DXA usually measures AAC along with bone mineral density, which is readily available, has low radiation exposure and low cost, the measurement of vascular calcification may be a part of routine BMD screening in the elderly . In order to assess AAC severity, an AAC rating quantification method was described in the Framingham study subgroup (AAC scores) . In 2006, a simplified AAC-8 system was described based on the initial AAC-24 scores, which was rapid and mildly influenced by small calcification deposited in arterial segments . The AAC-8 scores were highly correlated with AAC-24 scores revealed by DXA scans or X-rays, and AAC-8 scores revealed by DXA scans and X-rays were consistent .
The pathophysiological mechanism of AAC is different from other vascular diseases and has not been elucidated [9, 10]. Factors such as phosphate accumulation, inflammation, hormonal changes, metabolic disturbances, and oxidative stress are associated with mineral deposits in vascular walls as osteoblasts differentiate into VSMC (vascular smooth muscle cells) . In addition, there are some other mechanisms related to AAC. For example, uptake of circulatory osteoprogenitors, transdifferentiation of adventitial pericytes and VSMC, apoptosis of vascular cells and formation of mineralizing matrix vesicles form apoptotic bodies, which act as nuclei of ectopic calcification . Nevertheless, these mechanisms are related to each other, which may be involved in alternative steps of a common biological pathway. Our study revealed that serum calcium and HDL levels were correlated with the severity of AAC, suggesting that calcium metabolism and HDL were involved in the formation of AAC. A biologically plausible explanation for such an observation may exist and warrant further investigation. The first in vitro study investigated the direct effect of HDL on calcification-VSMC identified HDL as an inhibitor of ALP expression . HDL inhibits inflammation, oxidative stress, and cholesterol efflux, but this effect is weakened by oxidation or glycosylation . oxHDL (oxidized HDL) promotes osteoblastic differentiation in the vasculature, while inhibiting differentiation in the bone via paraoxanase-1 activity , reaffirming the involvement of HDL modifications in their functionality. Recent strong evidence suggests that among the components of metabolic syndrome, blood pressure, HDL and blood glucose levels were apparently associated with AAC .
Calcium is a major player in mineral deposition in the mechanism of vascular calcification. Terai K et al. showed that the amounts of calcium in the calcified rats were significantly higher than those in rats without calcification . Tilakezi Tuersun et al. revealed that elevated serum PTH disrupted the energy metabolism of cardiomyocytes, leading to calcium overload, calcium metabolism disorder, vascular inflammation, oxidative stress and endothelial dysfunction through the activation of protein kinases A or C. And vascular damage, vascular fibrosis and calcification were further caused . CaMOS (Canadian Multi-center Osteoporosis Study) showed that older female calcium supplement users had significantly more rapid AAC progression over 5 years . Recent studies have shown that after parathyroidectomy, the calcium level of patients with end-stage renal disease fell dramatically and calcification progression slowed down . The results of our study are similar, suggesting that calcium metabolism may be directly related to AAC.
To further investigate the correlation between 25-hydroxyvitamin D and AAC, statistical analysis was performed, and it was found that 25-hydroxyvitamin D was closely correlated with plasma calcium and HDL levels. Recent studies have shown that 25-hydroxyvitamin D is related to the metabolism of serum calcium and HDL. 25-hydroxyvitamin D is known to be involved in calcium metabolism, and 25-hydroxyvitamin D induced hypercalcemia is linked with vascular calcification [35, 36]. A meta-analysis showed that 25-hydroxyvitamin D participated in lipid metabolism and it could reduce glucose levels and HDL concentrations . Rolf et al. identified 22 cross-sectional studies in Pubmed, and it was found that the serum levels of 25-hydroxyvitamin D and lipid were related to each other and serum 25-hydroxyvitamin D was positively correlated with HDL . Even in specific populations, 25-hydroxyvitamin D deficiency in postmenopausal women was associated with low HDL levels . Liyanage et al. suggested that parenteral administration of 25-hydroxyvitamin D leaded to an increase in plasma HDL levels . This suggests a direct correlation of 25-hydroxyvitamin D and HDL levels, but the specific mechanisms remain to be further investigated.
Moreover, our study showed that 25-hydroxyvitamin D was independently associated with AAC severity, even when stratified and subgroup analyses were performed. It has been known that 25-hydroxyvitamin D plays an important role not only in bone health via regulating phosphorus and calcium metabolism, but also in cardiovascular health. Interestingly, some human and animal studies have shown that the role of both 25-hydroxyvitamin D excess and deficiency in vascular calcification indicates a biphasic vascular “dose-response” curve [41, 42]. At present, studies on the relationship between vitamin D deficiency and vascular calcification mainly focus on patients with renal insufficiency, and a low 25-hydroxyvitamin D level is often detected in cases with chronic kidney disease. According to some longitudinal studies, a low 25-hydroxyvitamin D level is a risk factor for vascular calcification and mortality [43–45]. In a 4-year longitudinal study, it was found that severe 25-hydroxyvitamin D insufficiency or deficiency was related to a higher risk of progression of aortic calcification, which was four-fold higher than that in individuals with a normal 25-hydroxyvitamin D level . But another study showed that AAC progression was not affected by high-dose 25-hydroxyvitamin D in aged African American females . Although 25-hydroxyvitamin D deficiency induces vascular calcification, a high level of 25-hydroxyvitamin D may be related to poor outcomes. In NHANES III, a U-shaped relationship of 25-hydroxyvitamin D and mortality risk was indicated, and there was an increase in mortality, particularly in females, with 25-hydroxyvitamin D levels > 50 ng/ml . Whether this increases the incidence of AAC and causes cardiovascular events and thus increases all-cause mortality remains to be further studied. Interestingly, many studies have constructed models of vascular calcification in animals fed with excess 25-hydroxyvitamin D, and it is suggested a high level of 25-hydroxyvitamin D may cause vascular calcification [14, 49–51]. This may be because a higher level of 25-hydroxyvitamin D may regulate phosphate metabolism through Klotho gene product and fibroblast growth factor, which induce aortic calcification . Similarly, with increased doses of 25-hydroxyvitamin D, a U-shaped dose-response relationship was observed (inflection point: 45.8ng/mL and 146ng/mL). These results suggest that clinicians should be cautious when providing 25-hydroxyvitamin D supplementation. Because 25-hydroxyvitamin D has a suitable range, and both high and low levels of 25-hydroxyvitamin D may induce vascular calcification, which leads to undesirable clinical consequences. The mechanism underlying the association of 25-hydroxyvitamin D and AAC remains to be further confirmed.
In our mind, this is the first study to report a significant association between plasma 25-hydroxyvitamin D and AAC using nationally representative data. However, there are also some limitations in this study. First of all, in a cross-sectional trial, the causality could not be determined. The mechanism of this phenomenon has not been further studied. Secondly, data on cardiovascular diseases are also limited in NHANES, and they might not be representative of all cardiovascular diseases. In addition, the diagnosis of cardiovascular diseases is based on the complaints of the interviewees, and there is lack of clinical objective evidence. Therefore, AAC was not linked with the incidence of cardiovascular diseases in this study.