Glucagon-like peptide-1 receptor agonist exendin 4 ameliorates diabetes-associated vascular calcification by regulating mitophagy through the AMPK signaling pathway.

BACKGROUND: Vascular calcification (VC) is a complication in diabetes mellitus (DM) patients. Osteogenic phenotype switching of vascular smooth muscle cells (VSMCs) plays a critical role in diabetes-related VC. Mitophagy can inhibit phenotype switching in VSMCs. This study aimed to investigate the role of the glucagon-like peptide-1 receptor (GLP-1R) agonist exendin 4 (EX4) in mitophagy-induced phenotype switching. MATERIALS AND METHODS: The status of VC in T2DM mice was monitored using Von Kossa and Alizarin Red S (ARS) staining in mouse aortic tissue. Human aortic smooth muscle cells were cultured in high glucose (HG) and ß-glycerophosphate (ß-GP) conditioned medium. Accumulation of LC3B and p62 was detected in the mitochondrial fraction. The effect of EX4 in vitro and in vivo was investigated by knocking down AMPKα1. RESULTS: In diabetic VC mice, EX4 decreased the percentage of von Kossa/ARS positive area. EX4 inhibited osteogenic differentiation of HG/ß-GP-induced VSMCs. In HG/ß-GP-induced VSMCs, the number of mitophagosomes was increased, whereas the addition of EX4 restored mitochondrial function, increased the number of mitophagosome-lysosome fusions, and reduced p62 in mitochondrial frictions. EX4 increased the phosphorylation of AMPKα (Thr172) and ULK1 (Ser555) in HG/ß-GP-induced VSMCs. After knockdown of AMPKα1, ULK1 could not be activated by EX4. The accumulation of LC3B and p62 could not be reduced after AMPKα1 knockdown. Knockdown of AMPKα1 negated the therapeutic effects of EX4 on VC of diabetic mice. CONCLUSION: EX4 could promote mitophagy by activating the AMPK signaling pathway, attenuate insufficient mitophagy, and thus inhibit the osteogenic phenotype switching of VSMCs.

Analysis of factors influencing vascular calcification in peritoneal dialysis patients and their impact on long-term prognosis.

BACKGROUND: This study aims to investigate the influencing factors of vascular calcification in peritoneal dialysis (PD) patients and its relationship with long-term prognosis. METHODS: This retrospective cohort study included chronic kidney disease patients undergoing peritoneal dialysis at the Peritoneal Dialysis Center of Beijing Luhu Hospital, Capital Medical University, from January 2019 to March 2019. Demographic and clinical laboratory data, including serum sclerostin (SOST), calcium (Ca), phosphate (P), serum albumin (ALB), and intact parathyroid hormone (iPTH) levels, were collected. Abdominal aortic calcification (AAC) was assessed using abdominal lateral X-ray examination to determine the occurrence of vascular calcification, and patients were divided into the AAC group and Non-AAC group based on the results. RESULTS: A total of 91 patients were included in the study. The AAC group consisted of 46 patients, while the Non-AAC group consisted of 45 patients. The AAC group had significantly older patients compared to the non-AAC group (P < 0.001) and longer dialysis time (P = 0.004). Multivariable logistic regression analysis indicated that risk factors for vascular calcification in PD patients included dialysis time, diabetes, hypertension, and SOST. Kaplan-Meier survival analysis showed that the AAC group had a significantly higher mortality rate than the non-AAC group (χ2 = 35.993, P < 0.001). Multivariable Cox regression analysis revealed that dialysis time, diabetes and AAC were risk factors for all-cause mortality in peritoneal dialysis patients. CONCLUSION: Longer dialysis time, comorbid diabetes, comorbid hypertension, and SOST are risk factors for vascular calcification in PD patients. Additionally, AAC, longer dialysis time, and comorbid diabetes are associated with increased risk of all-cause mortality in peritoneal dialysis patients.

A case report of ventricular fibrillation following Shockwave intravascular lithotripsy during percutaneous coronary intervention.

BACKGROUND: Shockwave intravascular lithotripsy (S-IVL) is widely used during percutaneous coronary intervention (PCI) of calcified coronary arteries. Ventricular capture beats during S-IVL are common but arrhythmias are rare. CASE PRESENTATION: A 75-year-old woman was scheduled for PCI to a short, heavily calcified chronic total occlusion of the right coronary artery. After wiring of the occlusion, S-IVL was used to predilated the calcified stenosis. During S-IVL, the patient developed ventricular fibrillation twice. CONCLUSION: To our knowledge, this is only the second reported case of VF during S-IVL. Although very rare, it is important to be aware of this potential and serious complication.

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.

Calcifications in the descending thoracic aorta predict postoperative anastomotic leakages after esophagectomy for cancer.

BACKGROUND: Anastomotic leak is one of the most feared complications of esophagectomy. Previous studies have suggested a potential link between aortic calcifications detected on routine preoperative CT scans and increased risk of anastomotic leak after esophagectomy. This study aims to investigate whether clinicians' assessment of aortic calcifications can predict the occurrence of anastomotic leaks in patients undergoing esophagectomy for cancer. METHODS: A long-term follow-up was conducted on consecutive patients with esophageal cancer who underwent elective open esophagectomy at a Finnish tertiary hospital. Aortic calcifications were evaluated based on CT scans and categorized on a 0-3 scale reflecting the number of calcifications in the affected segment of the aorta. Reviewers assessing the calcifications were blinded to clinical details and postoperative outcomes. RESULTS: The study included 97 patients (median age: 64 years and range: 43-78; 20% female), with a median follow-up time of 1307 (2-1540) days. Among them, 22 patients (23%) had postoperative anastomotic leak. We observed a significant association between calcifications in the descending aorta and a higher risk of anastomotic leak (p = 0.007), as well as an earlier occurrence of leak postoperatively (p = 0.013). However, there was no association between aortic calcifications and increased mortality. CONCLUSIONS: Presence of calcifications in the descending aorta is independently associated with an increased risk of anastomotic leaks following esophagectomy for cancer. Identifying patients at higher risk for this complication could facilitate appropriate pre- and postoperative interventions, as well as enable earlier diagnosis and treatment to mitigate the severity of the complication.

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.

Association of aortic stiffness with abdominal vascular and coronary calcifications in patients with stage 3 and 4 chronic kidney disease.

RATIONALE AND OBJECTIVES: Increased central (aortic) arterial stiffness has hemodynamic repercussions that affect the incidence of cardiovascular and renal disease. In chronic kidney disease (CKD) there may be an increase in aortic stiffness secondary to multiple metabolic alterations including calcification of the vascular wall (VC). The objective of this study was to analyze the association of central aortic pressures and aortic stiffness with the presence of VC in abdominal aorta (AAC) and coronary arteries(CAC). MATERIALS AND METHODS: We included 87 pacientes with CKD stage 3 and 4. Using applanation tonometry, central aortic pressures and aortic stiffness were studied. We investigated the association of aortic pulse wave velocity (Pvc-f) and Pvc-f adjusted for age, blood pressure, sex and heart rate (Pvc-f index) with AAC obtained on lumbar lateral radiography and CAC assessed by multidetector computed tomography. AAC and CAC were scored according to Kauppila and Agatston methods, respecti-vely. For the study of the association between Pvc-f index, Kauppila score, Agatston score, central aortic pressures, clinical parameters and laboratory data, multiple and logistic regression were used. We investigated the diagnosis performance of the Pvc-f index for prediction of VC using receiver-operating characteristic (ROC). RESULTS: Pvc-f and Pvc-f index were 11.3 ± 2.6 and 10.6 m/s, respectively. The Pvc-f index was higher when CKD coexisted with diabetes mellitus (DM). AAC and CAC were detected in 77% and 87%, respectively. Albuminuria (ß = 0.13, p = 0.005) and Kauppila score (ß = 0.36, p = 0.001) were independently associated with Pvc-f index. In turn, Pvc-f index (ß = 0.39, p = 0.001), DM (ß = 0.46, p = 0.01), and smoking (ß = 0.53; p = 0.006) were associated with Kauppila score, but only Pvc-f index predicted AAC [OR: 3.33 (95% CI: 1.6-6.9; p = 0.001)]. The Kauppila score was independently associated with the Agatston score (ß = 1.53, p = 0.001). The presence of AAC identified patients with CAC with a sensitivity of 73%, a specificity of 100%, a positive predictive value of 100% and a negative predictive value of 38%. The Vpc-f index predicted the presence of CAC [OR: 3.35 (95% CI: 1.04-10.2, p = 0.04)]. In the ROC curves, using the Vpc-f index, the AUC for AAC and CAC was 0.82 (95%CI: 0.71-0.93, p = 0.001) and 0.81 (95% CI: 0.67-0.96, p = 0.02), respectively. CONCLUSIONS: When stage 3-4 CKD coexists with DM there is an increase in aortic stiffness determined by the Vpc-f index. In stage 3-4 CKD, AAC and CAC are very prevalent and both often coexist. The Vpc-f index is independently associated with AAC and CAC and may be useful in identifying patients with VC in these territories.

Denosumab Decreases Epicardial Adipose Tissue Attenuation in Dialysis Patients with Secondary Hyperparathyroidism and Low Bone Mass.

INTRODUCTION: Denosumab preceding elective surgery is an alternative option when parathyroidectomy is not immediately possible. Denosumab (an osteoprotegerin mimic) may play a role in the cardiovascular system, which is reflected in the features of epicardial adipose tissue (EAT) and coronary artery calcification (CAC). METHODS: We investigated the effects of denosumab on EAT attenuation (EATat) and CAC in dialysis patients with secondary hyperparathyroidism (SHPT). This cohort study included patients on dialysis with SHPT. The baseline characteristics of dialysis patients and propensity score-matched non-dialysis patients were compared. Computed tomography scans of the dialysis patients (dialysis group with denosumab, n = 24; dialysis group without denosumab, n = 21) were obtained at baseline and at 6 months of follow-up. RESULTS: At baseline, the dialysis group patients had a higher EATat-median (-71.00 H ± 10.38 vs. -81.60 H ± 6.03; p < 0.001) and CAC (1,223 A [248.50-3,315] vs. 7 A [0-182.5]; p < 0.001) than the non-dialysis group. At follow-up, the dialysis group without denosumab showed an increase in Agatston score (1,319.50 A [238.00-2,587.50] to 1,552.00 A [335.50-2,952.50]; p = 0.001) without changes in EATat-median (-71.33 H ± 11.72 to -70.86 H ± 12.67; p = 0.15). The dialysis group with denosumab showed no change in Agatston score (1,132.2 A [252.25-3,260.5] to 1,199.50 A [324.25-2,995]; p = 0.19) but a significant decrease of EATat-median (-70.71 H ± 9.30 to -74.33 H ± 10.28; p = 0.01). CONCLUSIONS: Denosumab may reverse EATat and retard CAC progression in dialysis patients with SHPT.

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.

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.

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.

Deep learning-based prediction of coronary artery calcium scoring in hemodialysis patients using radial artery calcification.

OBJECTIVE: This study used random forest model to explore the feasibility of radial artery calcification in prediction of coronary artery calcification in hemodialysis patients. MATERIAL AND METHODS: We enrolled hemodialysis patients and performed ultrasound examinations on their radial arteries to evaluate the calcification status using a calcification index. All involved patients received coronary artery computed tomography scans to generate coronary artery calcification scores (CACS). Clinical variables were collected from all patients. We constructed both a random forest model and a logistic regression model to predict CACS. Logistic regression model was used to identify the risk factors of radial artery calcification. RESULTS: One hundred eighteen patients were included in our analysis. In random forest model, the radial artery calcification index, age, serum C-reactive protein, body mass index (BMI), diabetes, and hypertension history were related to CACS based on the average decrease of the Gini coefficient. The random forest model achieved a sensitivity of 76.9%, specificity of 75.0%, and area under receiver operating characteristic of 0.869, while the logistic regression model achieved a sensitivity of 75.2%, specificity of 68.7%, and area under receiver operating characteristic of 0.742 in prediction of CACS. Sex, BMI index, smoking history, hypertension history, diabetes history, and serum total calcium were all the risk factors related to radial artery calcification. CONCLUSIONS: A random forest model based on radial artery calcification could be used to predict CACS in hemodialysis patients, providing a potential method for rapid screening and prediction of coronary artery calcification.

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.

Association of Serum Osteoprotegerin With Vascular Calcification, and Cardiovascular and Graft Outcomes in Kidney Transplant Patients: Results From the KNOW-KT.

BACKGROUND: Vascular calcification and stiffness contribute to increased cardiovascular morbidity in patients with chronic kidney disease. This study investigated associations between serum osteoprotegerin (OPG) levels and vascular calcification or stiffness to assess cardiovascular and graft outcomes in kidney transplant patients. METHODS: The KoreaN cohort study for Outcome in patients With Kidney Transplantation was a prospective multicenter cohort study. Serum OPG levels were measured at baseline and 3 y after transplantation in 1018 patients. Patients were classified into high and low OPG groups according to median serum OPG levels. The median follow-up duration was 93.5 mo. RESULTS: The mean age was 45.8 ±â€…11.7 y and 62.9% were men. Patients with high OPG had significantly higher coronary artery calcium scores, abdominal aortic calcification scores, and brachial-ankle pulse wave velocities than those with lower OPG; these parameters remained significant for 5 y after transplantation. The 3-y OPG levels were lower than baseline values ( P < 0.001) and were positively correlated ( r = 0.42, P < 0.001). Multivariate Cox regression analysis showed that high OPG levels were significantly associated with posttransplant cardiovascular events ( P = 0.008) and death-censored graft loss ( P = 0.004). Similar findings regarding posttransplant cardiovascular events ( P = 0.012) and death-censored graft loss ( P = 0.037) were noted in patients with high OPG at the 3-y follow-up. Mediation analyses revealed that coronary artery calcium scores, abdominal aortic calcification scores, and brachial-ankle pulse wave velocities could act as mediators between serum OPG levels and posttransplant cardiovascular events. CONCLUSIONS: Serum OPG concentration is associated with vascular calcification and stiffness and could be a significant risk factor for cardiovascular outcomes and graft loss in patients undergoing kidney transplantation.

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.

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.