Vascular calcification is a pathological process of calcium and phosphate salts accumulation within the arterial wall. It involves mainly two forms, intimal calcification in atherosclerosis and cardiac valve calcification, and artery tunica media calcification (also known as Mönckeberg sclerosis) in aging, diabetes mellitus, and chronic kidney disease mediated calcification, with various degrees overlap of them [13, 14]. Vascular medial calcification increases vascular wall hardness and reducing vascular compliance. Aortic medial calcification induces cardiac pressure overload, leading to cardiovascular events such as congestive heart failure. According to previous studies [2–4], CVD was the leading cause of mortality in both RA and AS patients. The cardiovascular lesions in RA patients are characterized by earlier and more severe arterial calcification, as well as increased incidence and mortality of non-ischemic heart failure but not the incidence of atheromatous plaque [8, 10]. AS patients also manifest accelerated atherosclerosis, arterial stiffness and myocardial infarction after adjustment of traditional CVD risk factors [15, 16]. These data applaud that vascular calcification, especially aortic calcification may be an underlying mechanism of CVD in RA and AS patients.
This study evaluated the aortic calcification profiles in RA, AS patients and healthy controls, using a standard computerized tomography calcification score of the ascending aorta, aortic arch and thoracic aorta. The results showed that the aortic calcification scores (ACS) were elevated in all subgroups of RA patients than in sex and age-matched healthy controls. As if for AS, only females with age ≤ 50 years had higher ACS level. Meanwhile, all subgroups of AS patients had lower ACSs than RA patients, except for the female ≤ 50 years subgroup. RA increased the risk of aortic calcification by 4.72 (95% CI 2.78–7.99) fold after adjustment for age and sex, while AS generally did not (Table 2). Thus, RA patients had more severe aortic calcification than AS patients and controls, especially male and female in advanced age; only young female AS patients had aortic calcification level comparable with RA patients and higher than controls. These results support the previous clinical epidemiologic studies [2, 10, 15].
We further explored possible determinants for aortic calcification in all participants. Logistic regression analysis showed that only advanced age, male sex and FBG were independent risk factors for aortic calcification in healthy controls (Figure). Unlikely in studies concerning atherosclerosis [17], dislipidemia defined as high level of LDL-C, serum triglyceride and low level of HDL-C was not associated risk factor for aortic calcification in the present study. This implies a pathogenesis of calcification diversely from atherosclerosis. Although male sex had more severe coronary artery calcification score as reported by a Korean study [18], no convincing explanations available so far. Aging attributes to vascular calcification through multifaceted mechanisms [19]. Several researchers reported similar results that advanced age and FBG were independently related to aortic calcification in non-rheumatic population [20–23]. The common explanation underlies aging and diabetes is systemic inflammation [9, 24]..
Advanced age as a risk factor for aortic calcification was consistent in RA and AS patients, as it was in controls. AS patients had lower level of FBG, which may be a confounding factor for the ACS in this group. While other traditional factors like TG, LDL-C, FBG and SU were generally decreased and not involved in aortic calcification in either RA or AS patients. These data indicate that disease associated factors participate in developing arterial calcification in these patients. Disease duration and DAS28 (CRP) were impact factors for ACS in RA patients, and CRP and co-morbidities in AS patients. All these parameters are criteria for disease activity related systemic inflammation. Therefore, our study implies that chronic systemic inflammation may be the main contributors for aortic calcification in these patients. Recent studies have established that inflammatory joint diseases are associated with an increased risk of CVD development related in part to the chronic systemic inflammation, which is often marked in RA and usually moderate in AS [25]. Female AS patients had a higher CVD risk, with an OR of 5.75 in females and 2.85 in males [26, 27]. Our data are completely consistent with these research and might provide the pathological explanation for them.
RA and AS are all chronic inflammatory diseases that may affect multiple systems of the body, including the vascular bed. A recent prospective study reported that women with RA had increased risks of total and CVD mortality compared with those without RA (HR = 1.40 and 1.45, respectively) [28]. While another study from Netherlands showed that patients of early-onset RA under tight controlled treatment did not [29]. A cohort study revealed a doubled incidence of heart failure and an increased risk of mortality attributable to heart failure in patients with RA, with the risk of heart failure associated with RF positivity, repeatedly high ESR, severe extra-articular manifestations and corticosteroid use, and a protective effect against heart failure with methotrexate use [30]. Although data are limited, studies have confirmed that low disease activity of AS did not promote vascular calcification, and inflammatory related indicators were associated with increased mortality in patients with AS [13, 14]. Taking together, all these data suggested that the clinical markers of high systemic inflammation level confer an additional risk for CVD among these patients.
Rho et al further reported that vascular calcification did not associated with Framingham risk scores, nor the existence of diabetes mellitus; and only IL-6 and TNFα were independent risk factors for coronary artery calcification in RA patients [31]. IL-6 and TNFα are the key inflammatory cytokines indentified in RA and AS. IL-6 is a biopleiotropic cytokine and can induce multiple systematic effects, like hypoalbuminemia, anemia, apoptosis, weakness, dyslipidemia and the production of CRP in hepatocytes. CRP is closely related to inflammatory activity, CVD and other co-morbidities in RA [32, 33]. More and more studies including ours have shown that patients with RA and AS tend to have low TC and LDL-C levels, as well as low HDL-C level [34–36]. They found that there was a negative correlation between CRP and HDL-C levels in active RA and AS, which was consistent with the results of this study (r=-0.262, P = 0.001 in RA; r=-0.270, P = 0.007 in AS). Thus, our study also showed a systemic inflammatory profile prominently labeled by serum CRP levels in both RA and AS patients. Meanwhile, evidences of the relationship between IL-6 and vascular calcification are spring up [37]. Co-morbidities reflect the degree of target organ involvement of the disease. 53.2% of RA patients with high disease activity were complicated with other conditions at the disease onset, of which 23% developed other co-morbidities during followed up [38, 39]. This study found that the co-morbidity frequency tended to be a contributor to vascular calcifications in those patients (with OR = 2.88, 95% CI 0.95–8.74 in RA, and OR = 2.80, 95% CI 1.29–6.11 in AS), which was consistent with the previous studies. Aortic calcification induced mainly by systemic inflammation might be the key problem and the most important contributor to cardiovascular death in RA and AS.
We didn’t find any relationships between ACS and other disease related criteria, like RF and ACPA in RA, or HLA-B27 in AS. Apparently, RF, ACPA and HLA-B27 are more likely immunological disorders contributing to disease initiation rather than tissue inflammation [40]. Serum concentration of RF and ACPA will change the ESR level and made it not well consistent with CRP, which is a well-established marker of inflammation. This explained our results that ESR was in dependent with CRP and correlated with ACS in AS, but not in RA patients.
This pilot study has several limitations. Firstly, because this is a cross-sectional study, it’s hard to draw a causal conclusion of systemic inflammation on the aortic calcification. Longitudinal studies and research addressing the underlying mechanisms are needed. Secondly, although this study suggests aortic calcification score as a marker for systemic inflammation, we cannot build the normal range of ACS in age and sex-matched healthy controls given the insufficient sample size. The third, detailed changes of the cardiovascular system should be profiled to provide more clinical information, as well as the cytokine spectrum.