High Vascular Calcification Research Articles

The Calcimimetic Calindol Prevents High Phosphate-Induced Vascular Calcification by Upregulating Matrix GLA Protein

Background: High serum phosphate (Pi) levels represent a major issue in dialysis patients, because associate with secondary hyperparathyroidism, vascular calcification (VC), and cardiovascular outcomes. In this population, calcimimetics are used to control secondary hyperparathyroidism, hyperphosphatemia, and, more recently, to delay the progression of VC. The aim of this in vitro study was to investigate the direct effects of the calcimimetic calindol on the progression of high Pi-induced VC. Methods: Rat vascular smooth muscle cells (VSMCs) were incubated with high Pi concentrations, and the effects of calindol were investigated on vascular calcium deposition and VSMC osteoblastic differentiation. Results: Calindol inhibited calcium deposition concentration-dependently with a maximal inhibition of 64.0 ± 5.2% achieved at 100 n<smlcap>M</smlcap>. Furthermore, calindol was able to partially prevent the high Pi-induced bone morphogenic protein 2 (BMP-2) expression upregulation (32.4 ± 4.6% of inhibition; p < 0.01). Interestingly, the pretreatment with calindol enhanced the matrix Gla protein (MGP) gene expression significantly, compared to high Pi-treated cells (40.2 ± 6.6% of increase, p < 0.01). Conclusions: In conclusion, we demonstrated that the calcimimetic calindol prevents high Pi-induced VC by affecting osteoblastic differentiation in vitro. In particular, the inhibitory effect of calindol on VC is probably due to its stimulatory role on the calcium-sensing receptor, leading to an increase in the synthesis of MGP by VSMCs.

Serum phosphate and hip bone mineral density as additional factors for high vascular calcification scores in a community-dwelling: The São Paulo Ageing & Health Study (SPAH)

ObjectiveTo analyze the association between abdominal aortic calcification scores (AACS) and bone metabolism parameters in a well-characterized general population of older adults. BackgroundSeveral studies suggest a link between bone mineral metabolism disorders and vascular calcification; although only few of them analyze bone mineral density(BMD), laboratory bone markers and cardiovascular parameters at the same time and none were done in a miscegenated population. MethodsThis cross-sectional study included 815 subjects ≥65years old. The risk factors for osteoporosis and cardiovascular disease as well as a wide array of demographic and lifestyle characteristics were collected using a standardized questionnaire. BMD was measured by DXA. Kauppila's method was used to quantify the AAC score (AACS) by spine X-rays. Laboratory analyses were also performed. ResultsAAC was observed in 63.2% of subjects with a median AACS of 2 (IQR: 0–7). AACS were categorized in quartiles and the highest quartile of AACS (>7) were compared with the three lower quartiles of AACS (≤7). Logistic regression analysis was performed using parameters with statistical significance in the univariate analysis. The best logistic regression model revealed that AACS>7 was negatively associated with femoral neck BMD and positively associated with phosphorus, adjusted by age, current smoking, LDL, and arterial hypertension in the elderly community-dwelling population. ConclusionsWe identified that higher serum phosphate levels and lower hip BMD are independent bone variables that are associated with elevated vascular calcification scores, supporting the search for effective prevention and treatment strategies that may simultaneously reduce these modifiable risk factors in older subjects.

The combination of lanthanum chloride and the calcimimetic calindol delays the progression of vascular smooth muscle cells calcification

Phosphate (Pi)-binders are commonly used in dialysis patients to control high Pi levels, that associated with vascular calcification (VC). The aim of this study was to investigate the effects of lanthanum chloride (LaCl3) on the progression of high Pi-induced VC, in rat vascular smooth muscle cells (VSMCs). Pi-induced Ca deposition was inhibited by LaCl3, with a maximal effect at 100μM (59.0±2.5% inhibition). Furthermore, we studied the effects on VC of calcium sensing receptor (CaSR) agonists. Gadolinium chloride, neomycin, spermine, and the calcimimetic calindol significantly inhibited Pi-induced VC (55.9±2.2%, 37.3±4.7%, 30.2±5.7%, and 63.8±5.7%, respectively). To investigate the hypothesis that LaCl3 reduces the progression of VC by interacting with the CaSR, we performed a concentration–response curve of LaCl3 in presence of a sub-effective concentration of calindol (10nM). Interestingly, this curve was shifted to the left (IC50 9.6±2.6μM), compared to the curve in the presence of LaCl3 alone (IC50 19.0±4.8μM). In conclusion, we demonstrated that lanthanum chloride effectively reduces the progression of high phosphate-induced vascular calcification. In addition, LaCl3 cooperates with the calcimimetic calindol in decreasing Ca deposition in this in vitro model. These results suggest the potential role of lanthanum in the treatment of VC induced by high Pi.

Vascular calcification score on plain radiographs of the feet as a predictor of peripheral arterial disease in patients with chronic kidney disease

The incidence of lower extremity amputation is increasing in patients with chronic kidney disease (CKD), but symptoms of peripheral arterial disease (PAD) in patients with CKD are uncommon. The aim of the current study was to assess the value of the vascular calcification (VC) score on plain radiographs of the feet for the prediction of PAD in patients with CKD. We recruited 102 patients with CKD (24 pre-dialysis, 58 hemodialysis [HD], and 20 peritoneal dialysis [PD]). We defined the VC score on the plain radiographs of the feet as follows: score 0, no calcification; score 1, the length of the VC is <5 cm in a single foot or <2 cm in both feet; and score 2, the length of the VC is >5 cm in a single foot or >2 cm in both feet. We evaluated the atherosclerotic calcified plaques of the femoral or popliteal artery with Doppler ultrasonography and compared it with the VC score. Patients with high VC scores showed more atherosclerotic calcified plaques in the femoral or popliteal artery (P < 0.01). The prevalence of PAD in patients with CKD was closely related with the VC score (P < 0.01). PAD was associated with diabetes, a higher hsCRP, and a lower total cholesterol level (P < 0.01). The VC score was a significant predictor of the presence of PAD (odds ratio: 6.66, P < 0.001). Asymptomatic CKD patients, including those on HD and PD, may have PAD and routine testing by plain radiographs of the feet followed by Doppler ultrasonography are of pivotal significance, especially if the patients are diabetic.

Uncarboxylated matrix Gla protein (ucMGP) is associated with coronary artery calcification in haemodialysis patients

Matrix gamma-carboxyglutamate (Gla) protein (MGP) is a potent local inhibitor of cardiovascular calcification and accumulates at areas of calcification in its uncarboxylated form (ucMGP). We previously found significantly lower circulating ucMGP levels in patients with a high vascular calcification burden. Here we report on the potential of circulating ucMGP to serve as a biomarker for vascular calcification in haemodialysis (HD) patients. Circulating ucMGP levels were measured with an ELISA-based assay in 40 HD patients who underwent multi-slice computed tomography (MSCT) scanning to quantify the extent of coronary artery calcification (CAC). The mean ucMGP level in HD patients (193 +/- 65 nM) was significantly lower as compared to apparently healthy subjects of the same age (441 +/- 97 nM; p < 0.001) and patients with rheumatoid arthritis (RA) without CAC (560 +/- 140 nM; p < 0.001). Additionally, ucMGP levels correlated inversely with CAC scores (r = -0.41; p = 0.009), and this correlation persisted after adjustment for age, dialysis vintage and high-sensitivity C-reactive protein (hs-CRP). Since circulating ucMGP levels are significantly and inversely correlated with the extent of CAC in HD patients, ucMGP may become a tool for identifying HD patients with a high probability of cardiovascular calcification.