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Medial vascular calcification has emerged as a putative key factor contributing to the excessive cardiovascular mortality of patients with chronic kidney disease (CKD). Hyperphosphatemia is considered a decisive determinant of vascular calcification in CKD. A critical role in initiation and progression of vascular calcification during elevated phosphate conditions is attributed to vascular smooth muscle cells (VSMCs), which are able to change their phenotype into osteo-/chondroblasts-like cells. These transdifferentiated VSMCs actively promote calcification in the medial layer of the arteries by producing a local pro-calcifying environment as well as nidus sites for precipitation of calcium and phosphate and growth of calcium phosphate crystals. Elevated extracellular phosphate induces osteo-/chondrogenic transdifferentiation of VSMCs through complex intracellular signaling pathways, which are still incompletely understood. The present review addresses critical intracellular pathways controlling osteo-/chondrogenic transdifferentiation of VSMCs and, thus, vascular calcification during hyperphosphatemia. Elucidating these pathways holds a significant promise to open novel therapeutic opportunities counteracting the progression of vascular calcification in CKD.

Provision of non-invasive vascular imaging results to individuals has been shown to improve cardiovascular disease risk factor control: its impact on diet remains uncertain. In this two-arm, single-blind, parallel, 12-week randomized controlled trial, 240 participants, 57.5% females aged 60–80 y had abdominal aortic calcification and clinical assessments performed at a hospital clinic. Participants were randomized 1:1 to receive (intervention n  = 121) or not (control n  = 119) their calcification results. Both groups received educational resources on cardiovascular disease risk control and were unblinded to the intervention. Outcome measures were performed at baseline and 12 weeks. The primary outcomes of the study were changes in fruit and vegetable intake measures over 12 weeks assessed using plasma carotenoid concentrations (biomarkers of FV intake) and a food frequency questionnaire. Secondary outcomes included 12-week changes in other aspects of the diet, physical activity, body weight, blood pressure, heart rate, lipid profile, glucose concentrations, estimated cardiovascular disease risk score, and medication use. Between-group differences were tested using linear mixed-effects regression. There were no between-group differences in the primary outcomes at 12 weeks: plasma carotenoids (mean difference +0.03 µg/mL [95%CI −0.06, 0.13]) and fruit and vegetable intakes (+18 g/d [−37, 72]). However, the provision of calcification results led to between-group differences in serum total (−0.22 mmol/L [−0.41, −0.04]) and non-HDL (−0.19 mmol/L [−0.35, −0.03]) cholesterol, and estimated cardiovascular disease risk score (−0.24% [−0.47, −0.02]). No between-group differences were seen for other secondary outcomes. In this work, providing vascular imaging results did not improve diet but did improve some cardiovascular disease risk factors (Australian and New Zealand Clinical Trials Registry ACTRN12618001087246). It is unclear whether providing the results of abdominal aortic calcification imaging to patients improves diet parameters. This randomized trial shows that this intervention does not lead to improvements in fruit and vegetable intake, while showing an effect on some cardiovascular disease risk factors used as secondary outcomes.

Vascular calcification (VC), which is categorized by intimal and medial calcification, depending on the site(s) involved within the vessel, is closely related to cardiovascular disease. Specifically, medial calcification is prevalent in certain medical situations, including chronic kidney disease and diabetes. The past few decades have seen extensive research into VC, revealing that the mechanism of VC is not merely a consequence of a high-phosphorous and -calcium milieu, but also occurs via delicate and well-organized biologic processes, including an imbalance between osteochondrogenic signaling and anticalcific events. In addition to traditionally established osteogenic signaling, dysfunctional calcium homeostasis is prerequisite in the development of VC. Moreover, loss of defensive mechanisms, by microorganelle dysfunction, including hyper-fragmented mitochondria, mitochondrial oxidative stress, defective autophagy or mitophagy, and endoplasmic reticulum (ER) stress, may all contribute to VC. To facilitate the understanding of vascular calcification, across any number of bioscientific disciplines, we provide this review of a detailed updated molecular mechanism of VC. This encompasses a vascular smooth muscle phenotypic of osteogenic differentiation, and multiple signaling pathways of VC induction, including the roles of inflammation and cellular microorganelle genesis.

PurposeVascular calcification (VC) is an independent risk factor for cardiovascular disease in hemodialysis patients while Matrix GLA protein (MGP) is one of the most potent inhibitors of VC and its activation is vitamin K dependent. The aim of this study is to investigate the role of oral vitamin K2 supplementation in the prevention of VC progression in haemodialysis patients.MethodsWe conducted a prospective randomized interventional study in patients on hemodialysis. Patients were randomly assigned to either receiving orally 200 μgr of vitamin K2 (vitamin K2/MK-7, Solgar) every day for 1 year or no treatment. Uncarboxylated MGP (uc-MGP) concentrations were quantified using ELISA at randomization, at 3 and at 12 months. Aortic calcification was evaluated using Agatston score after an abdominal computed tomography scan that was performed at the beginning and at 12 months of follow-up.ResultsThere were 102 patients that were randomized. After 1 year of follow-up, 22 patients from the vitamin K2 group and 30 patients from the control group were included in the analysis. After 3 months of treatment, uc-MGP values remained unchanged in the vitK2 group but after 1 year were reduced by 47% (p = 0.005). Furthermore, uc-MGP at 1 year was increased by 12% in the control group. At 1 year, vitK2 group had significantly lower values of uc-MGP in comparison to controls (p = 0.03). Agatston score was increased significantly both in vitamin K2 and control group at 1 year with no difference between groups.ConclusionsOral administration of vitamin K2 in patients on haemodialysis reduced serum uc-MGP levels but did not have an effect in the progression of aortic calcification.

Coronary artery calcification is common among patients undergoing percutaneous coronary intervention (PCI), and severe coronary artery lesion calcification is associated with increased procedural complexity, stent under-expansion, and high rates of intraprocedural complications and out-of-hospital adverse events. Whether calcium ablation before stent implantation can mitigate these adverse events is not currently established. We aimed to prospectively compare orbital atherectomy with a balloon angioplasty-based strategy before stent implantation for the treatment of severely calcified coronary lesions. In this multicentre, open-label, randomised controlled trial conducted at 104 medical centres in the USA, patients (aged ≥18 years) with severely calcified coronary lesions were randomly assigned (1:1) to orbital atherectomy or balloon angioplasty before PCI with drug-eluting stents using a web-based system (block sizes of four and six) and stratified by intended treatment of single versus multiple lesions and enrolling site. Randomly assigned lesions were deemed by operators to be eligible for both treatment strategies. Operators and patients were not masked to treatment. The two powered coprimary study endpoints were target vessel failure at 1 year (a composite of cardiac death, target vessel myocardial infarction, or ischaemia-driven target vessel revascularisation) and post-procedural minimal stent area at the site of maximal calcification, as assessed by intravascular optical coherence tomography in an imaging patient cohort. Primary analyses were by intention-to-treat. The trial is registered at ClinicalTrials.govNCT03108456, and 2-year follow-up is ongoing. From March 27, 2017, to April 13, 2023, 2005 patients with 2492 lesions were randomly assigned to lesion preparation with orbital atherectomy (1008 patients with 1250 lesions) or balloon angioplasty (997 with 1242 lesions) before stent implantation. Median patient age was 70·0 years (IQR 64·0–76·0). 541 (27·0%) of 2005 patients were female and 1464 (73·0%) were male. Angiographically severe calcium was confirmed by the core laboratory in 1088 (97·1%) of 1120 lesions assigned to orbital atherectomy and 1068 (97·0%) of 1101 lesions assigned to balloon angioplasty. PCI was guided by intravascular imaging in 627 (62·2%) of 1008 patients in the orbital atherectomy group and 619 (62·1%) of 997 in the balloon angioplasty group. Target vessel failure events within 1 year occurred in 113 of 1008 patients in the orbital atherectomy group (1-year target vessel failure 11·5% [95% CI 9·7 to 13·7]) and in 97 of 997 patients in the balloon angioplasty group (10·0% [8·3 to 12·1]; absolute difference 1·5% [96% CI –1·4 to 4·4]; hazard ratio 1·16 [96% CI 0·87 to 1·54], p=0·28). Among those in the optical coherence tomography substudy cohort (276 patients with 286 lesions in the orbital atherectomy group and 279 patients with 292 lesions in the balloon angioplasty group), the mean minimal stent area at the site of maximal calcification was 7·67 mm2 (SD 2·27) in the orbital atherectomy group and 7·42 mm2 (2·54) in the balloon angioplasty group (mean difference 0·26 [99% CI –0·31 to 0·82]; p=0·078). Cardiac death events within 1 year occurred in 39 of 1008 patients in the orbital atherectomy group and in 26 of 997 in the balloon angioplasty group. Routine treatment with orbital atherectomy before drug-eluting stent implantation did not increase minimal stent area or reduce the rate of target vessel failure at 1 year compared with a balloon angioplasty-based approach in severely calcified lesions deemed eligible for both treatment strategies. These data support a balloon-first approach for most calcified coronary artery lesions that can be crossed and dilated before stent implantation, guided by intravascular imaging. Abbott Vascular (Abbott).

BackgroundIn the PREPARE-CALC trial, severely calcified lesion preparation with rotational atherectomy (RA) before biodegradable polymer sirolimus-eluting stent (SES) implantation demonstrated higher procedural success and comparable rates of acute lumen gain and late lumen loss compared to modified balloons (MB) (scoring/cutting). We aimed to analyze the 5-year outcomes of both lesion preparation strategies.MethodsPREPARE-CALC randomly assigned 200 patients 1:1 to MB or RA, followed by SES implantation. The principal endpoint of the current analysis was target vessel failure (TVF) at 5 years.ResultsAt 5 years, MB had comparable rates of TVF to RA (19% vs. 21%, HR 1.14, 95% CI 0.60–2.16, p = 0.687). Subgroup analysis showed a lesion length treatment interaction, favoring MB for short lesions and RA for long ones (p for interaction = 0.042). Target lesion revascularization (TLR) was significantly less common with RA (12 vs. 3%, HR 0.28, 95% CI 0.08–0.98, p = 0.048). In a multivariate analysis, RA was independently protective against TLR (adj. HR 0.17, 95% CI 0.04–0.78, p = 0.022), while ostial lesions were associated with higher TLR independent of treatment strategy (adj. HR 11.3, 95% CI 2.98–42.6, p < 0.001).ConclusionIn patients with severely calcified coronary lesions, using MB or RA for lesion preparation followed by biodegradable polymer SES implantation was associated with comparable rates of TVF at 5 years. However, a significant reduction of TLR was observed after RA. PREPARE-CALC is the first randomized trial showing potential clinical advantages of RA over MB during long-term follow-up.Clinical Trial RegistrationURL: https://www.clinicaltrials.gov. Unique identifier: NCT02502851.

Abdominal aortic calcification (AAC) detected on lateral vertebral fracture assessment is associated with increased cardiovascular risk. Vitamin D deficiency and toxicity have been linked with vascular calcification. The objective of this study was to determine the effect of high-dose vitamin D on the progression of AAC. The Physical Performance, Osteoporosis and vitamin D in African American Women (PODA) is a randomized, clinical trial examining the effect of vitamin D. There were 14.7% subjects with AAC in the vitamin D group, compared to 12.1% in the placebo group at baseline. The prevalence of extended AAC at baseline was 6.4% in the vitamin D group and 3.5% in the placebo group. The extended calcification scores over time were not different between groups. There was no association between AAC and serum 25(OH)D. However, PTH was associated with an increase in AAC in the placebo group.

Vascular calcification is considered to be a killer of the cardiovascular system, involved inflammation and immunity. There is no approved therapeutic strategy for the prevention of vascular calcification. Sinomenine exhibited anti-inflammatory and immunosuppressive effects. Objective of this study was to investigate the effect of sinomenine in vascular calcification and its potential molecular mechanism. Adenine-induced uremic rats were constructed and administrated with sinomenine. Optical clearing of aortas, alizarin red staining, von Kossa staining, calcification quantification, micro-CT analyses of vascular calcification were performed to analyze calcification in aortas. Administration of 40 mg/kg/d sinomenine effectively alleviated vascular calcification in uremic rats. The miRNA sequencing revealed differentially expressed miRNAs in aortas and bioinformatic analysis assisted with miRNA screening. We screened 9 differential expressed miRNAs and their predicted target genes. By qRT-PCR, we validated that the expression of rno-miR-143-5p was corresponding to our prediction. Sinomenine inhibited vascular smooth muscle cells (VSMCs) calcification, accompanied with miR-143-5p upregulation. MiR-143-5p mimic decreased VSMCs calcification in high phosphate condition. On the contrary, miR-143-5p inhibitor increased VSMCs calcification in high phosphate condition, which was inhibited by sinomenine. In chronic kidney disease patients with vascular calcification, the expression level of circulating miR-143-5p was lower than those without vascular calcification. Sinomenine significantly inhibited vascular calcification in VSMCs and uremic rat. MiR-143-5p was one of the collection of miRNAs modified by sinomenine in vascular calcification. Reduction of miR-143-5p in VSMCs was not only a concomitant phenomenon in pro-calcification condition but also contribute to VSMCs calcification. Circulating miR-143-5p was supposed to be a potential biomarker for vascular calcification in chronic kidney disease patients. In conclusion, sinomenine effectively alleviated vascular calcification, which was attributed to miR-143-5p regulation partly.

Severe coronary artery calcification has been associated with stent underexpansion, procedural complications, and increased rates of early and late adverse clinical events in patients undergoing percutaneous coronary intervention. To date, no lesion preparation strategy has been shown to definitively improve outcomes of percutaneous coronary intervention for calcified coronary artery lesions. ECLIPSE (NCT03108456) is a prospective, randomized, multicenter trial designed to evaluate two different vessel preparation strategies in severely calcified coronary artery lesions. The routine use of the Diamondback 360 Coronary Orbital Atherectomy System is compared with conventional balloon angioplasty prior to drug-eluting stent implantation. The trial aims to enroll approximately 2000 subjects with a primary clinical endpoint of target vessel failure, defined as the composite of cardiac death, target vessel-related myocardial infarction, or ischemia-driven target vessel revascularization assessed at 1 year. The co-primary endpoint is the acute post-procedural in-stent minimal cross-sectional area as assessed by optical coherence tomography in a 500-subject cohort. Enrollment is anticipated to complete in 2022 with total clinical follow-up planned for 2 years. ECLIPSE is a large-scale, prospective randomized trial powered to demonstrate whether a vessel preparation strategy of routine orbital atherectomy system is superior to conventional balloon angioplasty prior to implantation of drug-eluting stents in severely calcified coronary artery lesions.

Vascular calcification (VC) is an actively regulated pathological process that significantly increases the risk of cardiovascular events. As key cells of the innate immune system, macrophages play a dual role in VC through polarization into different phenotypes: Pro-inflammatory macrophages promote calcification by secreting pro-inflammatory factors, releasing apoptotic bodies, and producing extracellular vesicles (EVs); conversely, Anti-inflammatory macrophages inhibit calcification through anti-inflammatory factors, exosomes, plaque stabilization, and ATP/pyrophosphate (PPi) metabolism. However, under metabolic diseases such as diabetes, anti-inflammatory macrophages may exhibit pro-calcific properties. This review systematically summarizes the mechanisms of macrophage polarization in VC, discusses the application of macrophage-related biomarkers and imaging techniques in diagnosis, and highlights therapeutic strategies targeting macrophage polarization, recruitment, and activation. Finally, current challenges in dynamically monitoring macrophage polarization and context-dependent functional heterogeneity are outlined, and future research directions focusing on immunomodulation-based multi-target drug design and engineered cell therapies are proposed.