Intimal Calcification Research Articles

Osteocalcin and vascular calcification in hemodialysis patients: an observational cohort study.

Vascular calcification contributes to morbidity and mortality in patients with ESRD on maintenance hemodialysis. To study the relationship between osteocalcin and vascular calcification. 160 patients with ESRD on maintenance hemodialysis and 60 age-and sex-matched healthy controls were recruited. Serum vitamin K2 and osteocalcin both intact and undercarboxylated were measured. Transthoracic echocardiography was done for valvular calcification and thickening, and carotid duplex was done for carotid intimal medial calcification and thickening. Hemodialysis patients have higher median serum vitamin K2 (p < 0.001), higher undercarboxylated osteocalcin (p < 0.001). Only older age, duration of hypertension, and duration of established cardiovascular disease are associated with carotid media-intimal calcification. Old age is a strong predictor of carotid media intimal thickening. Female sex is associated with a valvular thickening. Functional vitamin K deficiency is present in maintenance hemodialysis patients and serum osteocalcin is not associated with cardiovascular calcification.

Role of Inflammation in Arterial Calcification.

Arterial calcification, characterized by calcium phosphate deposition in the arteries, can be divided into intimal calcification and medial calcification. The former is the predominant form of calcification in coronary artery plaques; the latter mostly affects peripheral arteries and aortas. Both forms of arterial calcification have strong correlations with adverse cardiovascular events. Intimal microcalcification is associated with increased risk of plaque disruption while the degree of burden of coronary calcification, measured by coronary calcium score, is a marker of overall plaque burden. Continuous research on vascular calcification has been performed during the past few decades, and several cellular and molecular mechanisms and therapeutic targets were identified. However, despite clinical trials to evaluate the efficacy of drug therapies to treat vascular calcification, none have been shown to have efficacy until the present. Therefore, more extensive research is necessary to develop appropriate therapeutic strategies based on a thorough understanding of vascular calcification. In this review, we mainly focus on intimal calcification, namely the pathobiology of arterial calcification, and its clinical implications.

Vascular Calcification in Chronic Kidney Disease: Distinct Features of Pathogenesis and Clinical Implication.

Chronic kidney disease (CKD) is associated with a higher prevalence of vascular calcification (VC) and cardiovascular disease. VC in CKD patients showed different pathophysiological features from those of the general population. The pathogenesis of VC in CKD is a highly organized process, and prior studies have suggested that patients with CKD have their own specific contributors to the phenotypic change of vascular smooth muscle cells (VSMCs), including uremic toxins, CKD-mineral and bone disease (CKD-MBD), inflammation, and oxidative stress. For the diagnosis and monitoring of VC in CKD, several imaging modalities, including plain radiography, ultrasound, and computed tomography have been utilized. VC in CKD patients has distinct clinical features and implications. CKD patients revealed a more intense and more prevalent calcification on the intimal and medial layers, whereas intimal calcification is predominantly observed in the general population. While a higher VC score is clearly associated with a higher risk of all-cause mortality and cardiovascular events, a greater VC score in CKD patients does not fully reflect the burden of atherosclerosis, because they have more calcification at equal volumes of atheromatous plaques. The primary goal of VC treatment in CKD is the prevention of VC progression, and the main management is to control the biochemical components of CKD-MBD. Cinacalcet and non-calcium-containing phosphate binders are the mainstay of VC prevention in CKD-MBD management. VC in patients with CKD is an ongoing area of research and is expected to advance soon.

ERK1/2 inhibition reduces vascular calcification by activating miR-126-3p-DKK1/LRP6 pathway.

Rationale: Vascular microcalcification increases the risk of rupture of vulnerable atherosclerotic lesions. Inhibition of ERK1/2 reduces atherosclerosis in animal models while its role in vascular calcification and the underlying mechanisms remains incompletely understood.Methods: Levels of activated ERK1/2, DKK1, LRP6 and BMP2 in human calcific aortic valves were determined. ApoE deficient mice received ERK1/2 inhibitor (U0126) treatment, followed by determination of atherosclerosis, calcification and miR-126-3p production. C57BL/6J mice were used to determine the effect of U0126 on Vitamin D3 (VD3)-induced medial arterial calcification. HUVECs, HAECs and HASMCs were used to determine the effects of ERK1/2 inhibitor or siRNA on SMC calcification and the involved mechanisms.Results: We observed the calcification in human aortic valves was positively correlated to ERK1/2 activity. At cellular and animal levels, U0126 reduced intimal calcification in atherosclerotic lesions of high-fat diet-fed apoE deficient mice, medial arterial calcification in VD3-treated C57BL/6J mice, and calcification in cultured SMCs and arterial rings. The reduction of calcification was attributed to ERK1/2 inhibition-reduced expression of ALP, BMP2 and RUNX2 by activating DKK1 and LRP6 expression, and consequently inactivating both canonical and non-canonical Wnt signaling pathways in SMCs. Furthermore, we determined ERK1/2 inhibition activated miR-126-3p production by facilitating its maturation through activation of AMPKα-mediated p53 phosphorylation, and the activated miR-126-3p from ECs and SMCs played a key role in anti-vascular calcification actions of ERK1/2 inhibition.Conclusions: Our study demonstrates that activation of miR-126-3p production in ECs/SMCs and interactions between ECs and SMCs play an important role in reduction of vascular calcification by ERK1/2 inhibition.

Histopathological characterization of intimal lesions and arterial wall calcification in the arteries of the leg of elderly cadavers.

IntroductionAlthough arteries of the leg have been studied in extensively diseased amputation specimens, little is known about the composition of vascular lesions present in the general population. The aim of this study was to describe the natural development of adaptive intimal thickening, atherosclerotic lesion development and vascular calcification in the leg of a general elderly population.Materials and MethodsTwo hundred and seventy postmortem samples from the popliteal and posterior tibial arteries of 14 elderly cadavers were studied histologically.ResultsAtherosclerotic lesions were more frequently observed in the popliteal (60%) than in the posterior tibial artery (34%; p < .0005). These atherosclerotic plaques were most often nonatheromatous (80% and 83% for popliteal and posterior tibial plaques, respectively). The atheroma's that were present were small (most <25% of plaque area). Atherosclerotic plaque calcification was observed more often in the popliteal (39%) than in the posterior tibial samples (17%; p < .0005). Medial arterial calcification was observed more often in the posterior tibial (62%) than in the popliteal samples (46%; p = .008). Plaque calcification and medial arterial calcification were not associated with lumen stenosis.ConclusionsIn the leg of elderly cadavers, the presence of atherosclerotic plaque and intimal calcification decreases from the proximal popliteal artery to the more distal posterior tibial artery and most atherosclerotic lesions are of the fibrous nonatheromatous type. In contrast, the presence and severity of medial calcification increases from proximal to distal.

Intracerebral hematoma expansion and intracranial internal carotid artery calcifications

Background and aimsPrediction of intracerebral hematoma expansion (IHE) is of critical importance during intracerebral hemorrhage (ICH) management. Given its suggested positive connection with cerebral microvascular disease status, intracranial internal carotid artery wall calcifications (ICAC) on admission computed tomography (CT) studies may contribute to prediction of IHE. MethodPresence, burden and type [as per Kockelkoren’s score] of ICAC were defined in admission CT and CT-angiography of 201 ICH patients [mean age: 70 ± 13 years, 44 % female]. A Kockelkoren’s score of <7 indicated intimal calcification [iICAC], while ≥7 indicated non-intimal [or medial] ones [mICAC]. IHE criteria were absolute volume increase of ≥12.5cc or ≥6cc, and relative increase ≥33 % or ≥26 %. ResultICAC was diagnosed in 79.6 % of ICH patients. ICAC status was not independent indicator of milder IHE (≥6cc and ≥26 % IHE, both in 27 %). Presence of contralateral mICAC was found to be an independent predictor for higher grade IHE (expβ = 3.44, 95 %CI: 1.47–8.04, for IHE ≥ 12.5cc, diagnosed in 14.4 %; and expβ = 2.67, 95 %CI: 1.29–5.55, for IHE ≥ 33 %, diagnosed in 24 %). Mortality (31 %) was higher in those with ipsilateral any type ICAC (36 % in mICAC, 38 % in iICAC, 17 % in no ICAC, p = 0.017), but this was not independent predictor in logistic regression. Similarly, medial ICAC in both ipsilateral (47 % vs. 31 %, p = 0.037) and contralateral (47 % vs. 30 %, p = 0.017) sides was associated with poorer prognosis (42 %) on univariate, but not multivariate analysis. ConclusionIntracranial ICA calcification is highly prevalent in ICH. mICAC may be associated with risk of “high amount” acute hematoma expansion, hospital mortality and poor prognosis.

Kv1.3 Channel, a Targetable Piece in the Complex Jigsaw Puzzle of Vascular Calcification?

In parallel with an unprecedented progress in vascular and stem cell biology during the past two decades, our understanding of vascular calcification has evolved from being perceived as a harmless, passive deposition of minerals to what we now consider a highly regulated, cell-mediated process that is strongly associated with chronic kidney disease (CKD) and confers increased risk for incident cardiovascular disease. A PubMed search of the term “vascular calcification” reveals an impressive exponential growth in the number of original articles published between 2000-2015, but this trend seems to have slowed down in the past 5-6 years. Studies have helped us understand that vascular calcification can engage a large number of key mediators and signalling pathways and that its anatomical and histological location can determine the type and severity of the clinical outcomes. Despite this significantly increased knowledge regarding the underlying pathophysiology, very little progress has been made when it comes to therapies and only a handful of interventional studies have documented any impact on vascular calcification other than modest effects in slowing down the process. The reasons for this lack of translational progress are many, including a somewhat conventional view of vascular calcification with most interventions aiming at restoring or reverting the uremic environment or targeting calcification too late in the process. In this issue of Function, Cazana-Perez et al provide new mechanistic insight in the regulation of vascular calcification, directing our attention to the vascular smooth muscle cell (VSMC), one of the main drivers in both medial and intimal calcification. (Less)

Intracranial artery calcifications: Risk factors and association with cardiovascular disease and cognitive function

Background and aimswe know little about clinical outcomes of arterial calcifications. This study investigates the risk factors of intracranial artery calcifications and its association with cardiovascular disease and cognitive function. Methodspatients were recruited from a Dutch memory clinic, between April 2009 and April 2015. The intracranial internal carotid artery (iICA) and basilar artery were analysed on the presence of calcifications. Calcifications in the iICA were also assessed on severity and location in the tunica intima or tunica media. Using logistic regression, risk factors of intracranial artery calcifications were analysed, as well as the association of these calcifications with cardiovascular disease, cognitive function and type of cognitive disorder (including subjective cognitive impairment, mild cognitive impairment and dementia). Cognitive function was assessed with the Cambridge Cognitive Examination. Results1992 patients were included (median age: 78.2 years, ±40% male). The majority of patients had calcifications in the iICA (±95%). Basilar artery calcifications were less prevalent (±8%). Risk factors for cerebral intracranial calcifications were age (p < 0.001), diabetes mellitus (medial iICA, p = 0.004), hypertension (intimal iICA, p < 0.001) and basilar artery, p = 0.019) and smoking (intimal iICA, p = 0.008). iICA calcifications were associated with stroke and intimal calcifications also with myocardial infarction. Intracranial artery calcifications were not associated with cognitive function or type of cognitive disorder. Conclusionthe majority of memory clinic patients had intracranial artery calcifications. Cardiovascular risk factors are differentially related to medial or intimal iICA calcifications. iICA calcifications were associated with myocardial infarction and stroke, but not with cognitive outcomes.

Intimal and medial calcification in relation to cardiovascular risk factors.

PurposeTo assess specific risk factors and biomarkers associated with intimal arterial calcification (IAC) and medial arterial calcification (MAC).MethodsWe conducted a cross-sectional study in patients with or at risk of vascular disease from the SMART study(n = 520) and the DCS cohort(n = 198). Non-contrast computed tomography scanning of the lower extremities was performed and calcification in the femoral and crural arteries was scored as absent, predominant IAC, predominant MAC or indistinguishable. Multinomial regression models were used to assess the associations between cardiovascular risk factors and calcification patterns. Biomarkers for inflammation, calcification and vitamin K status were measured in a subset of patients with IAC(n = 151) and MAC(n = 151).ResultsFemoral calcification was found in 77% of the participants, of whom 38% had IAC, 28% had MAC and 11% were scored as indistinguishable. The absolute agreement between the femoral and crural arteries was high(69%). Higher age, male sex, statin use and history of coronary artery disease were associated with higher prevalences of femoral IAC and MAC compared to absence of calcification. Smoking and low ankle-brachial-index (ABI) were associated with higher prevalence of IAC and high ABI was associated with less IAC. Compared to patients with IAC, patients with MAC more often had diabetes, have a high ABI and were less often smokers. Inactive Matrix-Gla Protein was associated with increased MAC prevalence, while osteonectin was associated with decreased risk of MAC, compared to IAC.ConclusionsWhen femoral calcification is present, the majority of the patients have IAC or MAC throughout the lower extremity, which have different associated risk factor profiles.

Diagnosing Calciphylaxis: A Review With Emphasis on Histopathology.

Calciphylaxis is a cutaneous vasculopathy with high morbidity and mortality characterized by vascular intimal fibrosis, calcification, stenosis, thrombosis, and eventual tissue death due to ischemia. Histopathologic diagnosis is often difficult, frequently necessitating multiple tissues samples due to lack of specific histopathologic features and subtle changes on biopsies of early lesions. In this study, we review the reported clinical and histopathologic features of calciphylaxis, correlating them with relevant imaging, ancillary studies, and pathophysiology. Although many histopathologic changes seen in calciphylaxis are also reported in other conditions (eg, Mönckeberg sclerosis, lupus panniculitis, pancreatic panniculitis, and peripheral artery disease), calcification of subcutaneous small vessels, thrombosis and/or ischemic changes, pseudoxanthoma elasticum-like changes in the subcutis, and perieccrine calcification may serve as helpful clues. von Kossa and Alizarin red stains can assist in the identification of subtle calcification. Netlike calcification of the affected blood vessels on imaging further supports the diagnosis. Studies into the pathophysiology of calciphylaxis are ongoing and will hopefully facilitate the development of additional diagnostic adjuncts to increase sensitivity and specificity for the diagnosis of this disease.

CT calcification patterns of peripheral arteries in patients without known peripheral arterial disease

PurposeIn the last few years histologic studies of peripheral arteries have shown that both intimal and medial calcifications are found in patients in an early, asymptomatic stage and that differentiation between medial and intimal calcifications is possible. The aim of this study was to assess the computed tomography (CT) calcification characteristics in peripheral arteries and to explore potential patterns in subjects without peripheral arterial disease (PAD). MethodRetrospectively, 204 patients without known PAD were studied. The thin slice CT-imaging characteristics severity, annularity, thickness and continuity were scored in the following arteries: plantar and dorsal, crural, femoro-popliteal, iliac and the abdominal aorta. Interrelation was assessed using linear regression and significance was tested by Chi-Square tests. ResultsIn the crural arteries two calcification patterns with strong associations were found. Pattern 1: continuous-annular 93.5 % (29/31), continuous-thin and thin-annular both 73 % (27/37, p < 0.001) and pattern 2: thick-discontinuous 91.7 % (44/48), thick-dotted 68.8 % (33/48), patchy-dotted 59.3 % (16/27, p < 0.001). Similar associations were found in the femoro-popliteal artery, but not in the plantar, dorsal, iliac arteries and aorta. ConclusionsIn the crural and femoropopliteal arteries at least two morphological patterns can be distinguished on CT that, compared to a CT-histologically validated score, may represent an intimal and medial calcification pattern.

Visualization of Mineral-Targeted Alkaline Phosphatase Binding to Sites of Calcification In Vivo.

A mineral-targeted form of recombinant tissue-nonspecific alkaline phosphatase (TNAP), asfotase alfa, was approved multinationally as an enzyme replacement therapy for hypophosphatasia in 2015. Two reports to date have shown evidence of binding of this drug to mineralizing tissues using histochemistry and immunohistochemistry. Here, we sought to expand on those earlier studies by directly visualizing the in vivo binding of asfotase alfa conjugated with AnaTag HiLyte Fluor 750 or Alexa Fluor 647 fluorescent dye to sites of skeletal/dental mineralization and ectopic calcification. We utilized 40-day-old Tagln-Cre; HprtALPL/Y mice, a model of severe medial vascular calcification; Tie2-Cre; HprtALPL/Y mice, a model of severe intimal calcification; and sibling WT HprtALPL/Y mice, devoid of soft-tissue calcification. A single dose of 8 mg/kg labeled asfotase alfa was injected via the retro-orbital route. Skeletal tissues and soft organs were imaged ex vivo 2 days after the injection. Strong fluorescence signal was observed in all skeletal tissues (calvaria, vertebra, long bones, jaw, and mandibles) from mutant and WT mice. Fluorescence analysis of histological sections from bones revealed strong binding of asfotase alfa. Asfotase alfa binding to sites of ectopic calcification in the heart, aorta, and renal artery were found in both the Tagln-Cre; HprtALPL/Y and Tie2-Cre; HprtALPL/Y mice but not in WT mice. In addition, asfotase alfa binding was also found in the kidney stroma and brain of the Tie2-Cre; HprtALPL/Y mice. Our results show that fluorescence-labeled asfotase alfa administered in vivo binds not only to sites of skeletal and dental mineralization but also to sites of ectopic calcification in these animal models. © 2020 American Society for Bone and Mineral Research.

Impact of hepatitis virus infection on arterial calcification among incident hemodialysis patients

BackgroundThe impact of hepatitis virus infection on arterial calcification (AC) was not studied. ObjectiveTo study the prevalence, severity and distribution of AC in incident hemodialysis patients with hepatitis B and C viral infection. Cases and methods172 stage 5 CKD adults (98 male and 74 female) were included; 58 of them were seronegative for both hepatitis B and C (SN group), 48 were positive for hepatitis B virus infection (HBV group) and 66 were hepatitis C virus positive (HCV group). Beside histopathology of the obtained arterial samples, all these cases were examined for body mass index (BMI), serum calcium (Ca), phosphorus (P), alkaline phosphatase (AP), serum albumin, uric acid (UA), alanine transaminase (ALT), parathormone (PTH), fibroblast growth factor 23(FGF23), interleukin 6 (IL6), and 25 hydroxy vitamin D (25 (OH) vit D), hemoglobin concentration, and serum ferritin. Results86 (50%) of the cases had AC; 11 of them were in SN group (19%), 9 in HBV group (18.8%) and all the 66 HCV group (100%). In SN group, 4 had intimal calcification, 5 had medial calcification, and 2 had both intimal and medial calcification. In HBV group, 9 had intimal calcification, while no cases were encountered with either medial or both site calcifications. In HCV group, 16 had intimal calcification, 31 had medial calcification, and 19 had both intimal and medial calcification. Calcification was in the form of spots in one case in SN group, and 6 cases in HBV group, a single plaque of calcification in 5 cases of SN group, 3 cases of HBV group, and 16 cases of HCV group, multiple plaques were detected in 4 cases in SN group, and 31 cases in HCV group, and diffuse calcification in one case in SN group, and 19 cases in HCV group.In HBV group, calcification was only detected in patients with high viremia, while all patients with low or moderate viremia were devoid of calcification. In HCV group, all patients with low viremia had intimal solitary plaque of calcification, all patients with moderate viremia had multiple plaques of medial calcification, while all patients with high viremia had diffuse intimal and medial calcification. Both groups of viral hepatitis were significantly different in comparison to SN group in either distribution or calcification score (P<0.001 in all).HBV group had significantly lower serum P, CaxP and PTH in comparison to SN group (4.6±0.66 vs. 5.45±0.77mg/dL, 36.4±7.2 vs. 44.1±8.69, and 348±65.4 vs. 405.9±83.2pg/mL, P<0.001, <0.001, and 0.035 respectively). On the other hand, HCV group did not show any significant difference in any of the studied parameters compared to SN group. ConclusionHCV positive patients are more prone to develop AC that is more extensive. HBV positive patients were less likely to have arterial medial calcification, probably related to lower serum phosphorus, CaxP product and PTH. HCV infection should be added as risk factor for AC among CKD patients. Further studies are needed to confirm these findings.

Matrix Gla protein is an independent predictor of both intimal and medial vascular calcification in chronic kidney disease

Matrix Gla protein (MGP) is a potent inhibitor of vascular calcification (VC) and requires carboxylation by vitamin K to exert calcification inhibition. Chronic kidney disease (CKD) patients undergo early vascular aging often involving extensive VC. The present cross-sectional study investigated the association between circulating dp-ucMGP levels, MGP expression in vascular tissue and MGP polymorphisms. In 141 CKD stage 5 patients, CAC score was significantly increased in the highest tertile of dp-ucMGP (p = 0.002), and a high medial VC score was associated with elevated dp-ucMGP levels. MGP vascular expression was associated with increased circulating dp-ucMGP and CAC scores. MGP SNP analysis revealed that patients homozygous for the C allele of the rs1800801 variant had a higher CAC score (median 15 [range 0–1312]) compared to patients carrying a T allele (median 0 [range 0–966] AU). These results indicate that plasma levels of dp-ucMGP are an independent predictor of increased VC in CKD5 patients and correlate with both higher CAC scores and degree of medial calcification. Additionally, high vascular expression of MGP was associated with higher CAC scores and plasma dp-ucMGP levels. Taken together, our results support that MGP is involved in the pathogenesis of VC.

Vascular Calcification-New Insights Into Its Mechanism.

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.

Use of Tourniquet During Knee Arthroplasty in Patients With Radiographic Arterial Calcifications

BackgroundUse of tourniquet during total knee arthroplasty (TKA) in patients with radiographic arterial calcifications is controversial. Intimal arterial calcifications are feared to be associated with ischemic complications such as delayed wound healing and arterial thrombosis, whereas medial calcifications stiffen the arterial wall, possibly leading to tourniquet failure and increased blood loss. MethodsWe conducted a prospective cohort study to determine the incidence of tourniquet failure (inflated up to 300 mm Hg), blood transfusions, wound healing, and ischemic complications in thighs with and without arterial calcifications on preoperative radiographs, in 2548 consecutive primary TKAs conducted in our unit over a 5-year period. Eighty-six thighs showed vascular calcifications: 58 medial and 28 intimal. ResultsThighs with vascular calcifications had higher risk of tourniquet failure as compared to those without calcifications (P < .001), but with no significant increase in incidence of blood transfusions. All cases of tourniquet failure in the calcification group occurred in thighs with medial calcifications, whereas all cases of tourniquet failure in the control group occurred in obese patients. There was no difference in wound healing and ischemic complications in limbs with and without arterial calcifications. ConclusionThe presence of arterial calcifications on preoperative radiographs increases the risk of tourniquet failure at 300 mm Hg in patients undergoing TKA, with no significant increase in rate of blood transfusions, wound healing or ischemic complications.

Calcium phosphate bions: towards a pathogenetic concept

Supersaturation of blood with calcium and phosphate is associated with higher risk of major adverse cardiovascular events; however, pathophysiological basis of such association remains unclear. Upon an excess of serum calcium and phosphate, mineral chaperone fetuin-A aggregates mineral ions into calcium phosphate bions (CPB, alternatively termed calciprotein particles), which are irreversibly internalised by endothelial cells causing lysosome membrane permeabilisation, non-specific inflammatory response and cell death. Altogether, these processes contribute to pathological microenvironment potentiating endothelial dysfunction, osteochondrogenic differentiation of vascular smooth muscle cells, and adventitial inflammation which in turn culminate into intimal hyperplasia and medial arterial calcification. Albeit the correlation between increased CPB count in the blood and higher risk of cardiovascular events/cardiovascular death has initially been found in patients with chronic kidney disease, recent investigations suggest similar scenario in patients with arterial hypertension and coronary artery disease without renal dysfunction testifying to the general pathophysiological mechanism. Here we discuss the existing data on how CPB do form and how they affect the development of cardiovascular disease. We further consider advantages and shortcomings of the relevant experimental models as well as diagnostic significance of measuring CPB in the serum and clinical potential of anti-CPP therapies for the patients with chronic kidney disease, coronary artery disease, and cerebrovascular disease.

Macrophage galectin-3 enhances intimal translocation of vascular calcification in diabetes mellitus.

The clinical risks and prognosis of diabetic vascular intimal calcification (VIC) and medial calcification (VMC) are different. This study aims to investigate the mechanism of VIC/VMC translocation. Anterior tibial arteries were collected from patients with diabetic foot amputation. The patients were then divided into VIC and VMC groups. There were plaques in all anterior tibial arteries, while the enrichment of galectin-3 in arterial plaques in the VIC group was significantly higher than that in the VMC group. Furthermore, a macrophage/vascular smooth muscle cell (VSMC) coculture system was constructed. VSMC-derived extracellular vesicles (EVs) was labeled with fluorescent probe. After macrophages were pretreated with recombinant galectin-3 protein, the migration of VSMC-derived EVs and VSMC-derived calcification was more pronounced. And anti-galectin-3 antibody can inhibit this process of EVs and calcification translocation. Then, lentivirus (LV)-treated bone marrow cells (BMCs) were transplanted into apolipoprotein E-deficient (ApoE-/-) mice, and a diabetic atherosclerosis mouse model was constructed. After 15 wk of high-fat diet, ApoE-/- mice transplanted with LV-shgalectin-3 BMCs exhibited medial calcification and a concentrated distribution of EVs in the media. In conclusion, upregulation of galectin-3 in macrophages promotes the migration of VSMC-derived EVs to the intima and induces diabetic vascular intimal calcification.NEW & NOTEWORTHY The clinical risk and prognosis of vascular intimal and medial calcification are different. Macrophage galectin-3 regulates the migration of vascular smooth muscle cell-derived extracellular vesicles and mediates diabetic vascular intimal/medial calcification translocation. This study may provide insights into the early intervention in diabetic vascular calcification.

The Inhibitory Roles of Vitamin K in Progression of Vascular Calcification.

Vitamin K is a fat-soluble vitamin that is indispensable for the activation of vitamin K-dependent proteins (VKDPs) and may be implicated in cardiovascular disease (CVD). Vascular calcification is intimately associated with CV events and mortality and is a chronic inflammatory process in which activated macrophages promote osteoblastic differentiation of vascular smooth muscle cells (VSMCs) through the production of proinflammatory cytokines such as IL-1β, IL-6, TNF-α, and oncostatin M (OSM) in both intimal and medial layers of arterial walls. This process may be mainly mediated through NF-κB signaling pathway. Vitamin K has been demonstrated to exert anti-inflammatory effects through antagonizing NF-κB signaling in both in vitro and in vivo studies, suggesting that vitamin K may prevent vascular calcification via anti-inflammatory mechanisms. Matrix Gla protein (MGP) is a major inhibitor of soft tissue calcification and contributes to preventing both intimal and medial vascular calcification. Vitamin K may also inhibit progression of vascular calcification by enhancing the activity of MGP through facilitating its γ-carboxylation. In support of this hypothesis, the procalcific effects of warfarin, an antagonist of vitamin K, on arterial calcification have been demonstrated in several clinical studies. Among the inactive MGP forms, dephospho-uncarboxylated MGP (dp-ucMGP) may be regarded as the most useful biomarker of not only vitamin K deficiency, but also vascular calcification and CVD. There have been several studies showing the association of circulating levels of dp-ucMGP with vitamin K intake, vascular calcification, mortality, and CVD. However, additional larger prospective studies including randomized controlled trials are necessary to confirm the beneficial effects of vitamin K supplementation on CV health.

Distribution of Medial Calcification and Luminal Stenosis in Symptomatic Patients with Hemodialysis and Peripheral Artery Disease Using 3D Computed Tomography Angiography

Background: Vascular calcification, including medial and intimal calcification leading to luminal stenosis of the lower extremities are commonly associated with hemodialysis (HD), whereas their distribution has not been assessed comprehensively. Three-dimensional (3D) computed tomography angiography (CTA) may be a powerful imaging tool for detection of vascular calcification and arterial stenosis with high spatial resolution in HD patients and peripheral artery disease (PAD). Objectives: The aim of this study was to investigate the distribution of medial calcification and luminal stenosis in symptomatic patients with HD and PAD using 3D CTA. Patients and Methods: Forty-seven patients with HD and symptomatic PAD underwent 3D CTA of the lower extremities. We used 3D maximum intensity projection with and without subtraction by precontrast from postcontrast images in order to assess the medial calcification and luminal stenosis in the common, external, and internal iliac arteries, superficial femoral arteries, and lower limb arteries. Results: The external iliac artery (EIA) was significantly spared from both medial calcification and luminal stenosis, while the internal iliac, superficial femoral artery (SFA), and tibioperoneal arteries had either arterial disorders. Conclusion: The characteristic distribution of medial calcification and luminal stenosis, such as spared EIA and SFA involvement, is observed in patients with HD and symptomatic PAD by 3D CTA.