Effects of LP533401 on vascular and bone calcification in hyperlipidemic mice.

Peripheral serotonin levels are associated with cardiovascular disease risk. We previously found that serum serotonin levels are higher in hyperlipidemic mice than wild-type mice. Evidence also suggests that serotonin regulates biomineralization, in that serotonin treatment augments TNF-a-induced matrix calcification of aortic valve interstitial cells and that a selective inhibitor of peripheral serotonin, LP533401, rescues bone loss induced by ovariectomy in mice. Thus, in the present study, we examined the effects of LP533401 on both skeletal bone mineral density (BMD) and aortic calcification in both young and older hyperlipidemic mice susceptible to calcific atherosclerosis and bone loss. By serial in vivo microCT imaging, we assessed BMD and aortic calcification of Apoe-/- mice fed an atherogenic (high cholesterol) diet alone or mixed with LP533401. Results show that in the young mice, LP533401 blunted skeletal bone loss in lumbar vertebrae but not in femurs. LP533401 also blunted the initial development of aortic calcification but not its progression. Echocardiographic analysis showed that LP533401 blunted both hyperlipidemia-induced cardiac hypertrophy and left ventricular dysfunction. In the older mice, LP533401 increased the BMD of lumbar vertebrae but not of femurs. The aortic calcification progressed in both controls and LP533401-treated mice, but, at post-treatment, LP533401-treated mice had significantly less aortic calcification than the controls. These findings suggest that LP533401 mitigates adverse effects of hyperlipidemia on skeletal and vascular tissues in site- and stage-dependent manners.

A machine learning approach to predicting vascular calcification risk of type 2 diabetes: A retrospective study.

BACKGROUND: Recently, patients with type 2 diabetes mellitus (T2DM) have experienced a higher incidence and severer degree of vascular calcification (VC), which leads to an increase in the incidence and mortality of vascular complications in patients with T2DM. HYPOTHESIS: To construct and validate prediction models for the risk of VC in patients with T2DM. METHODS: Twenty-three baseline demographic and clinical characteristics were extracted from the electronic medical record system. Ten clinical features were screened with least absolute shrinkage and selection operator method and were used to develop prediction models based on eight machine learning (ML) algorithms (k-nearest neighbor [k-NN], light gradient boosting machine, logistic regression [LR], multilayer perception [(MLP], Naive Bayes [NB], random forest [RF], support vector machine [SVM], XGBoost [XGB]). Model performance was evaluated using the area under the receiver operating characteristic curve (AUC), accuracy, and precision. RESULTS: A total of 1407 and 352 patients were retrospectively collected in the training and test sets, respectively. Among the eight models, the AUC value in the NB model was higher than the other models (NB: 0.753, LGB: 0.719, LR: 0.749, MLP: 0.715, RF: 0.722, SVM: 0.689, XGB:0.707, p < .05 for all). The k-NN model achieved the highest sensitivity of 0.75 (95% confidence interval [CI]: 0.633-0.857), the MLP model achieved the highest accuracy of 0.81 (95% CI: 0.767-0.852) and specificity of 0.875 (95% CI: 0.836-0.912). CONCLUSIONS: This study developed a predictive model of VC based on ML and clinical features in type 2 diabetic patients. The NB model is a tool with potential to facilitate clinicians in identifying VC in high-risk patients.

CDK1 inhibition reduces osteogenesis in endothelial cells in vascular calcification.

Vascular calcification is a severe complication of cardiovascular diseases. Previous studies demonstrated that endothelial lineage cells transitioned into osteoblast-like cells and contributed to vascular calcification. Here, we found that inhibition of cyclin-dependent kinase (CDK) prevented endothelial lineage cells from transitioning to osteoblast-like cells and reduced vascular calcification. We identified a robust induction of CDK1 in endothelial cells (ECs) in calcified arteries and showed that EC-specific gene deletion of CDK1 decreased the calcification. We found that limiting CDK1 induced E-twenty-six specific sequence variant 2 (ETV2), which was responsible for blocking endothelial lineage cells from undergoing osteoblast differentiation. We also found that inhibition of CDK1 reduced vascular calcification in a diabetic mouse model. Together, the results highlight the importance of CDK1 suppression and suggest CDK1 inhibition as a potential option for treating vascular calcification.

Age differences in the association of body mass index-defined obesity with abdominal aortic calcification.

Objectives: In cardiovascular disease, previous studies have suggested young age as one of the reasons to explain the obesity paradox. This study attempts to provide a different opinion on this claim through unexpected findings. Methods: We used a cross-sectional analysis of the US nationally representative data, total of 10,175 participants were recruited in 2013-2014 from NHANES. A total of 947 participants were selected to be included in this study through inclusion criteria and exclusion criteria for statistical analysis of the relationship between obesity and abdominal aortic calcification(AAC). Smooth curve fitting and multivariate regression analyses were conducted to examine the associations of obesity with AAC after adjusting for age, gender and associated variates. Results: Depending on the age of the population, the relationship between obesity and AAC showed the different outcome. Obesity was associated with the lower risk of AAC among individuals older than 52 years of age. According to the difference of adjusted covariates, the AAC scores in the obesity group decreased by 0.92, 0.87, and 1.11 for 52 years old or older individuals. In particular, the risk of AAC was lower for patients with obesity with the following characteristics: male, low LDL, low triglyceride, DM, non-cancer patient, smoking, drinking, vigorous work activity, low annual household income, education of 9 - 11th grades and non-Hispanic white. Conclusions: In US, adults aged 52 years or older, obesity was associated with decreased AAC risk. Older age may be one potential reason for the obesity paradox.

Construction of a miR-15a-based risk prediction model for vascular calcification detection in patients undergoing hemodialysis.

Vascular calcification (VC) is highly prevalent in patients undergoing hemodialysis, and is a significant contributor to the mortality rate. Therefore, biomarkers that can accurately predict the onset of VC are urgently required. Our study aimed to investigate serum miR-15a levels in relation to VC and to develop a predictive model for VC in patients undergoing hemodialysis at the Beijing Friendship Hospital hemodialysis center between 1 January 2019 and 31 December 2020. The patients were categorized into two groups: VC and non-VC. Logistic regression (LR) models were used to examine the risk factors associated with VC. Additionally, we developed an miR-15a-based nomogram based on the results of the multivariate LR analysis. A total of 138 patients under hemodialysis were investigated (age: 58.41 ± 13.22 years; 54 males). VC occurred in 79 (57.2%) patients. Multivariate LR analysis indicated that serum miR-15a, age, and WBC count were independent risk factors for VC. A miR-15a-based nomogram was developed by incorporating the following five predictors: age, dialysis vintage, predialysis nitrogen, WBC count, and miR-15a. The receiver operating characteristic (ROC) curve had an area under the curve of 0.921, diagnostic threshold of 0.396, sensitivity of 0.722, and specificity of 0.932, indicating that this model had good discrimination. This study concluded that serum miR-15a levels, age, and white blood cell (WBC) count are independent risk factors for VC. A nomogram constructed by integrating these risk factors can be used to predict the risk of VC in patients undergoing hemodialysis.

Aortic valve and arterial calcification in patients with familial hypercholesterolemia.

Heterozygous familial hypercholesterolemia (heFH) is an autosomal dominant lipid metabolism disorder. Its prevalence is 1:250-1:300 people in the population. Patients with heFH have an up to 13-fold increased risk of premature coronary artery disease (CAD). If left untreated, men and women with heFH typically develop early CAD before the ages of 55 and 60, respectively. There is evidence that coronary artery calcification (CAC) and aortic valve calcification (AoVC) are more prevalent in FH patients than in the general population. It is documented that CAC and AoVC are predictors of increased risk of cardiovascular morbidity and mortality in heFH patients, like in the general population. However, the etiology and pathogenesis of vascular calcification in FH patients is not well understood. Risk factors for vascular calcification include age, increased levels of atherogenic lipoproteins, Lp(a), increased blood pressure, and inflammation. There are convincing data from clinical studies and animal atherosclerotic mouse models using low-density lipoprotein receptor (LDL-R) knockout mice that the vascular calcification processes in FH are associated with LDL-R mutations, probably partly due to a higher total cholesterol burden of FH subjects. Data from animal models as well as clinical studies indicate that the Wnt/beta-catenin pathway components and LDL receptor-related proteins 5 and 6 (LRP-5/6) might be involved in calcification processes in FH patients. The purpose of the review is to describe the prevalence of coronary and aortic calcification and its risk factors in FH patients. The review covers data about the role of the Wnt/beta-catenin pathway and factors modulating calcification processes.

The functional role of cellular senescence during vascular calcification in chronic kidney disease.

Vascular calcification (VC) has emerged as a key predictor of cardiovascular events in patients with chronic kidney disease (CKD). In recent years, an expanding body of research has put forth the concept of accelerated vascular aging among CKD patients, highlighting the significance of vascular cells senescence in the process of VC. Within the milieu of uremia, senescent vascular endothelial cells (VECs) release extracellular microvesicles (MV) that promote vascular smooth muscle cells (VSMCs) senescence, thereby triggering the subsequent osteogenic phenotypic switch and ultimately contributing to the VC process. In addition, senescent vascular progenitor or stem cells with diminished ability to differentiate into VECs and VSMCS, compromise the repair of vascular integrity, on the other hand, release a cascade of molecules associated with senescence, collectively known as the senescence-associated secretory phenotype (SASP), perpetuating the senescence phenomenon. Furthermore, SASP triggers the recruitment of monocytes and macrophages, as well as adjacent VECs and VSMCs into a pro-adhesive and pro-inflammatory senescent state. This pro-inflammatory microenvironment niche not only impacts the functionality of immune cells but also influences the differentiation of myeloid immune cells, thereby amplifying the reduced ability to effectively clear senescent cells of senescent macrophages, promoted calcification of VSMCs. The objective of this paper is to provide a comprehensive review of the contribution of vascular cell senescence to the emergence and advancement of VC. Gaining a comprehensive understanding of the involvement of cellular senescence within the vessel wall is pivotal, especially when it comes to its intersection with VC. This knowledge is essential for advancing groundbreaking anti-aging therapies, aiming to effectively mitigate cardiovascular diseases.

Liver and spleen predominantly mediate calciprotein particle clearance in a rat model of chronic kidney disease.

Calciprotein particles (CPPs) provide an efficient mineral buffering system to prevent the complexation of phosphate and calcium in the circulation. However, in chronic kidney disease (CKD), the phosphate load exceeds the mineral buffering capacity, resulting in the formation of crystalline CPP2 particles. CPP2 have been associated with cardiovascular events and mortality. Moreover, CPP2 have been demonstrated to induce calcification in vitro. In this study, we examined the fate of CPP2 in a rat model of CKD. Calcification was induced in Sprague-Dawley rats by 5/6 nephrectomy (5/6-Nx) combined with a high-phosphate diet. Control rats received sham surgery and high-phosphate diet. Twelve weeks after surgery, kidney failure was significantly induced in 5/6-Nx rats as determined by enhanced creatinine and urea plasma levels and abnormal kidney histological architecture. Subsequently, radioactive and fluorescent (FITC)-labeled CPP2 ([89Zr]Zr-CPP2-FITC) were injected intravenously to determine clearance in vivo. Using positron emission tomography scans and radioactive biodistribution measurements, it was demonstrated that [89Zr]Zr-CPP2-FITC are mainly present in the liver and spleen in both 5/6-Nx and sham rats. Immunohistochemistry showed that [89Zr]Zr-CPP2-FITC are predominantly taken up by Kupffer cells and macrophages. However, [89Zr]Zr-CPP2-FITC could also be detected in hepatocytes. In the different parts of the aorta and in the blood, low values of [89Zr]Zr-CPP2-FITC were detectable, independent of the presence of calcification. CPP2 are cleared rapidly from the circulation by the liver and spleen in a rat model of CKD. In the liver, Kupffer cells, macrophages, and hepatocytes contribute to CPP2 clearance.NEW & NOTEWORTHY Calciprotein particles (CPPs) buffer calcium and phosphate in the blood to prevent formation of crystals. In CKD, increased phosphate levels may exceed the buffering capacity of CPPs, resulting in crystalline CPPs that induce calcification. This study demonstrates that labeled CPPs are predominantly cleared from the circulation in the liver by Kupffer cells, macrophages, and hepatocytes. Our results suggest that targeting liver CPP clearance may reduce the burden of crystalline CPP in the development of vascular calcification.

Association between hemoglobin A1c and abdominal aortic calcification: results from the National Health and Nutrition Examination Survey 2013-2014.

BACKGROUND: Hemoglobin A1c (HbA1c), a "gold standard" for the assessment of glycemic control, was associated with an increased risk of cardiovascular disease and coronary artery calcification. However, its effects on abdominal aortic calcification (AAC) are uncertain. The present study comprehensively investigated the association between HbA1c and AAC in the 2013-2014 National Health and Nutrition Examinations Surveys. METHODS: Among 1,799 participants ≥ 40 years, dual-energy X-ray absorptiometry-derived AAC was quantified using the Kauppila score (AAC-24). Severe AAC was defined as a total AAC-24 > 6. Weighted linear regression models and logistic regression models were used to determine the effects of HbA1c on AAC. The restricted cubic spline model was used for the dose-response analysis. RESULTS: The mean AAC-24 of participants was 1.3, and 6.7% of them suffered from severe AAC. Both AAC-24 and the prevalence of severe AAC increased with the higher tertile of HbA1c (P < 0.001). Elevated HbA1c levels would increase the AAC-24 (ß = 0.73, 95% CI: 0.30-1.16) and the risk of severe AAC (OR = 1.63, 95% CI: 1.29-2.06), resulting in nearly linear dose-response relationships in all participants. However, this positive correlation were not statistically significant when participants with diabetes were excluded. Furthermore, subgroup analysis showed significant interactions effect between HbA1c and hypertension on severe AAC with the OR (95% CI) of 2.35 (1.62-3.40) for normotensives and 1.39 (1.09-1.79) for hypertensives (P for interaction = 0.022). CONCLUSION: Controlling HbA1c could reduce AAC scores and the risk of severe AAC. Glycemic management might be a component of strategies for preventing AAC among all participants, especially normotensives.

Establishment and evaluation of a nomogram prediction model for the risk of vascular calcification in stage 5 chronic kidney disease patients.

Vascular calcification (VC) is a common complication of chronic kidney disease (CKD) that has a detrimental effect on patients' survival and prognosis. The aim of this study was to develop and validate a practical and reliable prediction model for VC in CKD5 patients. The medical records of 544 CKD5 patients were reviewed retrospectively. Multivariate logistic regression analysis was used to identify the independent risk factors for vascular calcification in patients with CKD5 and then created a nomogram prediction model. The area under the receiver operating characteristic curve (AUC), Hosmer-Lemeshow test, and decision curve analysis (DCA) were used to assess model performance. The patients were split into groups with normal and high serum uric acid levels, and the factors influencing these levels were investigated. Age, BUN, SUA, P and TG were independent risk factors for vascular calcification in CKD5 patients in the modeling group (P < 0.05). In the internal validation, the results of model showed that the AUC was 0.917. No significant divergence between the predicted probability of the nomogram and the actual incidence rate (x2 = 5.406, P = 0.753) was revealed by the calibration plot and HL test, thus confirming that the calibration was satisfactory. The external validation also showed good discrimination (AUC = 0.973). The calibration chart and HL test also demonstrated good consistency. Besides, the correlation analysis of serum uric acid levels in all CKD5 patients revealed that elevated uric acid levels may be related to gender, BUN, P, and TG.

Phosphonoformic acid reduces hyperphosphatemia-induced vascular calcification via Pit-1.

OBJECTIVE: This study aimed to examine the mechanism of hyperphosphatemia-induced vascular calcification (HPVC). METHODS: Primary human aortic smooth muscle cells and rat aortic rings were cultured in Dulbecco's modified Eagle's medium supplemented with 0.9 mM or 2.5 mM phosphorus concentrations. Type III sodium-dependent phosphate cotransporter-1 (Pit-1) small interfering RNA and phosphonoformic acid (PFA), a Pit-1 inhibitor, were used to investigate the effects and mechanisms of Pit-1 on HPVC. Calcium content shown by Alizarin red staining, expression levels of Pit-1, and characteristic molecules for phenotypic transition of vascular smooth muscle cells were examined. RESULTS: Hyperphosphatemia induced the upregulation of Pit-1 expression, facilitated phenotypic transition of vascular smooth muscle cells, and led to HPVC in cellular and organ models. Treatment with Pit-1 small interfering RNA or PFA significantly inhibited Pit-1 expression, suppressed phenotypic transition, and attenuated HPVC. CONCLUSIONS: Our findings suggest that Pit-1 plays a pivotal role in the development of HPVC. The use of PFA as a Pit-1 inhibitor has the potential for therapeutic intervention in patients with HPVC. However, further rigorous clinical investigations are required to ensure the safety and efficacy of PFA before it can be considered for widespread implementation in clinical practice.

Phosphate in Cardiovascular Disease: From New Insights Into Molecular Mechanisms to Clinical Implications.

Hyperphosphatemia is a common feature in patients with impaired kidney function and is associated with increased risk of cardiovascular disease. This phenomenon extends to the general population, whereby elevations of serum phosphate within the normal range increase risk; however, the mechanism by which this occurs is multifaceted, and many aspects are poorly understood. Less than 1% of total body phosphate is found in the circulation and extracellular space, and its regulation involves multiple organ cross talk and hormones to coordinate absorption from the small intestine and excretion by the kidneys. For phosphate to be regulated, it must be sensed. While mostly enigmatic, various phosphate sensors have been elucidated in recent years. Phosphate in the circulation can be buffered, either through regulated exchange between extracellular and cellular spaces or through chelation by circulating proteins (ie, fetuin-A) to form calciprotein particles, which in themselves serve a function for bulk mineral transport and signaling. Either through direct signaling or through mediators like hormones, calciprotein particles, or calcifying extracellular vesicles, phosphate can induce various cardiovascular disease pathologies: most notably, ectopic cardiovascular calcification but also left ventricular hypertrophy, as well as bone and kidney diseases, which then propagate phosphate dysregulation further. Therapies targeting phosphate have mostly focused on intestinal binding, of which appreciation and understanding of paracellular transport has greatly advanced the field. However, pharmacotherapies that target cardiovascular consequences of phosphate directly, such as vascular calcification, are still an area of great unmet medical need.

PRMT3 methylates HIF-1α to enhance the vascular calcification induced by chronic kidney disease.

BACKGROUND: Medial vascular calcification is commonly identified in chronic kidney disease (CKD) patients and seriously affects the health and life quality of patients. This study aimed to investigate the effects of protein arginine methyltransferase 3 (PRMT3) on vascular calcification induced by CKD. METHODS: A mice model of CKD was established with a two-step diet containing high levels of calcium and phosphorus. Vascular smooth muscle cells (VSMCs) were subjected to ß-glycerophosphate (ß-GP) treatment to induce the osteogenic differentiation as an in vitro CKD model. RESULTS: PRMT3 was upregulated in VSMCs of medial artery of CKD mice and ß-GP-induced VSMCs. The inhibitor of PRMT3 (SGC707) alleviated the vascular calcification and inhibited the glycolysis of CKD mice. Knockdown of PRMT3 alleviated the ß-GP-induced osteogenic transfomation of VSMCs by the repression of glycolysis. Next, PRMT3 interacted with hypoxia-induced factor 1α (HIF-1α), and the knockdown of PRMT3 downregulated the protein expression of HIF-1α by weakening its methylation. Gain of HIF-1α reversed the PRMT3 depletion-induced suppression of osteogenic differentiation and glycolysis of VSMCs. CONCLUSION: The inhibitory role of PRMT3 depletion was at least mediated by the regulation of glycolysis upon repressing the methylation of HIF-1α.

Vascular calcification inhibitors and cardiovascular events in peritoneal dialysis patients.

The prevalence of cardiovascular diseases is high among patients with chronic kidney disease (CKD) and peritoneal dialysis (PD) patients, which increases morbidity and mortality in this population and represents a significant financial burden for both the patients and the healthcare systems. Vascular calcification (VC) is associated with increased morbidity and mortality and VC risk is higher in patients with CKD than in healthy individuals. Calcification inhibitors, compounds that inhibit VC, were discovered as a result of efforts to explain why some patients are spared. It was found that certain proteins (e.g., fetuin-A, osteopontin, osteoprotegerin, bone morphogenetic protein-7) inhibit calcification in dialysis patients. In this narrative review, we provide an overview of known calcification inhibitors, describe the relevant regulatory mechanisms, and discuss their relation to VC development in PD patients.

Effect of renin-angiotensin system inhibitors on cardiovascular events in hemodialysis patients with hyperphosphatemia: A post hoc analysis of the LANDMARK trial.

INTRODUCTION: The clinical benefits of renin-angiotensin system inhibitors (RASi) in patients undergoing hemodialysis remain obscure. METHODS: This is a post hoc cohort analysis of the LANDMARK trial investigate whether RASi use was associated with cardiovascular events (CVEs) and all-cause mortality. A total of 2135 patients at risk for vascular calcification were analyzed using a Cox proportional hazards model with propensity-score matching. RESULTS: The risk of CVEs was similar between participants with RASi use at baseline and those without RASi use at baseline and between participants with RASi use during the study period and those without RASi use during the study period. No clinical benefits of RASi use on all-cause mortality were observed. Serum phosphate levels were significantly associated with the effect of RASi on CVEs. CONCLUSIONS: RASi use was not significantly associated with a lower risk of CVEs or all-cause mortality in hemodialysis patients at risk of vascular calcification.

Orbital atherectomy safety and efficacy: A comparative analysis of ostial versus non-ostial calcified coronary lesions.

BACKGROUND: The safety and efficacy of coronary orbital atherectomy (OA) for treatment of ostial lesions are not yet fully established. We sought to evaluate (OA) treatment of severely calcified ostial and non-ostial lesions. METHODS: A retrospective analysis of subjects treated with OA for severely calcified ostial and non-ostial lesions, at the Mount Sinai Medical Center, Miami Beach, Florida (MSMCMB) from January 2014 to September 2020, was completed. Study baseline characteristics, lesion and vessel characteristics, procedural outcomes, and in-hospital major adverse cardiovascular events (MACE) were analyzed and compared. RESULTS: A total of 609 patients that underwent PCI with OA were identified. The majority of patients (81.9 %) had non-ostial lesions, while 16.6 % had ostial lesions (of which 2.8 % classified as aorto-ostial) and 1.5 % had unknown lesion anatomy. The mean age of the overall cohort was 74.0 ± 9.3 years, and 63.5 % were male. All patients received drug-eluting stent (DES) placement, and the overall freedom from MACE was 98.5 %, with no significant difference observed between the ostial and non-ostial groups. The freedom from cardiac death and MI was also similar between the two groups. There were low rates of bleeding complications and severe angiographic complications, and no persistent slow flow/no reflow was reported. CONCLUSIONS: This study demonstrated no significant differences in in-hospital MACE outcomes between patients with ostial versus non-ostial lesions, indicating that OA is a safe and effective treatment option for both lesion types, including those classified as aorto-ostial.

Shh-Gli2-Runx2 inhibits vascular calcification.

BACKGROUND: In patients with chronic kidney disease (CKD), vascular calcification (VC) is common and is associated with a higher risk of all-cause mortality. Shh, one ligand for Hedgehog (Hh) signaling, participates in osteogenesis and several cardiovascular diseases. However, it remains unclear whether Shh is implicated in the development of VC. METHODS: Inorganic phosphorus 2.6 mM was used to induce vascular smooth muscle cells (VSMCs) calcification. Mice were fed with adenine diet supplement with 1.2% phosphorus to induce VC. RESULTS: Shh was decreased in VSMCs exposed to inorganic phosphorus, calcified arteries in mice fed with an adenine diet, as well as radial arteries from patients with CKD presenting VC. Overexpression of Shh inhibited VSMCs ostosteoblastic differentiation and calcification, whereas its silencing accelerated these processes. Likewise, mice treated with smoothened agonist (SAG; Hh signaling agonist) showed alleviated VC, and mice treated with cyclopamine (CPN; Hh signaling antagonist) exhibited severe VC. Additionally, overexpression of Gli2 significantly reversed the pro-calcification effect of Shh silencing on VSMCs, suggesting that Shh inhibited VC via Gli2. Mechanistically, Gli2 interacted with Runx2 and promoted its ubiquitin proteasomal degradation, therefore protecting against VC. Of interest, the pro-degradation effect of Gli2 on Runx2 was independent of Smurf1 and Cullin4B. CONCLUSIONS: Our study provided deeper insight to the pathogenesis of VC, and Shh might be a novel potential target for VC treatment.

Chronic kidney disease mineral bone disorder in childhood and young adulthood: a 'growing' understanding.

Chronic kidney disease (CKD) mineral and bone disorder (MBD) comprises a triad of biochemical abnormalities (of calcium, phosphate, parathyroid hormone and vitamin D), bone abnormalities (turnover, mineralization and growth) and extra-skeletal calcification. Mineral dysregulation leads to bone demineralization causing bone pain and an increased fracture risk compared to healthy peers. Vascular calcification, with hydroxyapatite deposition in the vessel wall, is a part of the CKD-MBD spectrum and, in turn, leads to vascular stiffness, left ventricular hypertrophy and a very high cardiovascular mortality risk. While the growing bone requires calcium, excess calcium can deposit in the vessels, such that the intake of calcium, calcium- containing medications and high calcium dialysate need to be carefully regulated. Normal physiological bone mineralization continues into the third decade of life, many years beyond the rapid growth in childhood and adolescence, implying that skeletal calcium requirements are much higher in younger people compared to the elderly. Much of the research into the link between bone (de)mineralization and vascular calcification in CKD has been performed in older adults and these data must not be extrapolated to children or younger adults. In this article, we explore the physiological changes in bone turnover and mineralization in children and young adults, the pathophysiology of mineral bone disease in CKD and a potential link between bone demineralization and vascular calcification.

Extent of Abdominal Aortic Calcification Is Associated With Incident Rapid Weight Loss Over 5 Years: The Perth Longitudinal Study of Ageing Women.

BACKGROUND: Abdominal aortic calcification (AAC), a marker of vascular disease, is associated with disease in other vascular beds including gastrointestinal arteries. We investigated whether AAC is related to rapid weight loss over 5 years and whether rapid weight loss is associated with 9.5-year all-cause mortality in community-dwelling older women. METHODS: Lateral spine images from dual-energy x-ray absorptiometry (1998/1999) were used to assess AAC (24-point AAC scoring method) in 929 older women. Over 5 years, body weight was assessed at 12-month intervals. Rapid weight loss was defined as >5% decrease in body weight within any 12-month interval. Multivariable-adjusted logistic regression was used to assess AAC and rapid weight loss and Cox regression to assess the relationship between rapid weight loss and 9.5-year all-cause mortality. RESULTS: Mean±SD age of women was 75.0±2.6 years. During the initial 5 years, 366 (39%) women presented with rapid weight loss. Compared with women with low AAC (24-point AAC score 0-1), those with moderate (24-point AAC score 2-5: odds ratio, 1.36 [95% CI, 1.00-1.85]) and extensive (24-point AAC score 6+: odds ratio, 1.59 [95% CI, 1.10-2.31]) AAC had higher odds for presenting with rapid weight loss. Results remained similar after further adjustment for dietary factors (alcohol, protein, fat, and carbohydrates), diet quality, blood pressure, and cholesterol measures. The estimates were similar in subgroups of women who met protein intake (n=599) and physical activity (n=735) recommendations (extensive AAC: odds ratios, 1.81 [95% CI, 1.12-2.92] and 1.58 [95% CI, 1.02-2.44], respectively). Rapid weight loss was associated with all-cause mortality over the next 9.5 years (hazard ratio, 1.49 [95% CI, 1.17-1.89]; P=0.001). CONCLUSIONS: AAC extent was associated with greater risk for rapid weight loss over 5 years in older women, a risk for all-cause mortality. Since the association was unchanged after taking nutritional intakes into account, these data support the possibility that vascular disease may play a role in the maintenance of body weight.

Effect of iron administration on the aortic iron content and vascular calcification in phosphorus-loaded chronic kidney disease rats.

BACKGROUND: Cardiovascular disease (CVD) is a major cause of morbidity and mortality in patients with chronic kidney disease (CKD) and could be related to oxidative stress. Vascular calcification (VC) has been established as a critical risk factor for accelerated CVD. In CKD, phosphorus (Pi), iron (Fe) and Nrf2 are modulators of VC and important agonists and antagonists of oxidative stress. The aim of this study was to determine whether Fe administration, which is commonly used to treat renal anemia, affects aortic Fe overload and VC, and whether Nrf2 and its related genes, ferritin H and HIF-1α, are involved in the development of VC. METHODS: A CKD model was created in rats by administering adenine and simultaneously feeding a high-Pi diet. In addition to control and CKD rats without Fe administration (No-Fe group), Fe was administered orally (PO-Fe group) or intraperitoneally (IP-Fe group) to CKD animals to clarify the effects of Fe administration on the aortic Fe and calcium (Ca) contents and the involvement of Nrf2 and its induced antioxidative proteins, ferritin H and HIF-1α, in VC. RESULTS: The aortic Fe content increased significantly in the IP-Fe group, which was closely correlated with liver HAMP (hepcidin) expression in all animals. Fe administration had no significant effect on the aortic Ca and Pi contents regardless of the route of Fe administration. The aortic mRNA level of Nrf2 was significantly increased in the IP-Fe group and correlated with serum Pi levels and aortic Fe contents, which could respond to oxidative stress. Notably, the mRNA level of Nrf2 was also significantly correlated with the mRNA levels of ferritin H and HIF-1α. Since we could not measure Nrf2 protein levels in this study, we confirmed the upregulation of HMOX1 and NQO1 mRNA expression in parallel with Nrf2 mRNA. CONCLUSION: Parenteral Fe administration increased aortic Fe in parallel with the liver HAMP mRNA level but did not affect VC. Aortic Nrf2 mRNA levels correlated significantly with aortic Fe and serum Pi levels and with aortic mRNA levels of ferritin H and HIF-1α as well as HMOX1 and NQO1.