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Introduction: It is currently unclear whether chronic kidney disease (CKD) and the decrease in renal function can influence the risk of venous thromboembolism (VTE) recurrence., Materials and Methods: We performed an ambispective observational study on 409 patients with a previous episode of VTE. All the patients were included in the retrospective analysis whereas a subgroup of 260 individuals, without history of recurrence and that stopped oral anticoagulation, were then followed-up for a mean of 52.3±20.7months., Results: At the enrollment, subjects with history of recurrent VTE were prevalently male with higher blood pressure and lower eGFR. Prevalence of CKD (defined as eGFR<60ml/min/1.73m 2 ) was higher in patients with previous VTE recurrence with an adjusted OR of 5.69 (IC95% 2.17-14.90, p<0.001) compared to patients with normal eGFR. Similar findings were obtained from the prospective study where an adjusted 5.32 HR for VTE recurrence was seen in patients with CKD compared to subjects with normal renal function (IC95% 1.49-18.95, p=0.010). An increase in the risk of recurrent VTE was also observed in patients with mild decrease in renal function (eGFR 60-90 vs ≥90ml/min/1.73m 2 adjusted HR 2.84, IC95% 1.13-7.11, p=0.025). Moreover, a multivariate Cox regression analysis including eGFR as continuous variable showed that renal function decrease was independently associated with the risk of VTE recurrence (p=0.001)., Conclusions: CKD and mild decrease in renal function are associated with a significant increase in the risk of recurrent VTE., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Aim of this study was to evaluate in a long follow-up the carotid artery remodelling in a cohort of young hypertensive subjects having good blood pressure (BP) control. We studied 20 grade I hypertensives (HT) by assessing the B-mode ultrasound of mean carotid intima-media thickness (mean-IMT) and maximum IMT (M-MAX) in each carotid artery segment (common, bulb, internal), bilaterally. We compared their ultrasound measurements with those recorded 5 and 10 years earlier. While the first 5-year follow-up was observational, in the second 5-year follow-up, lifestyle modifications and/or pharmacological therapy were started to obtain well-controlled BP levels. Office BP was measured at the time of the ultrasound studies and every 6 months during the follow-up. BP levels were: 10 years 144/91 mmHg, 5 years 143/90 mmHg and 129 ± 79 mmHg at the time of the study. In the first 5-year observational follow-up, both mean-IMT and M-MAX increased (Δ 0.116 and Δ 0.165 mm, respectively, p < 0.0005). In the 5-year intervention follow-up, characterized by well-controlled BP, mean-IMT slightly but significantly increased (Δ 0.084 mm, p = 0.004), whereas M-MAX remained stable (Δ 0.026 mm). In our HT, well-controlled BP levels were able to prevent pro-atherogenic remodelling (expressed by M-MAX). Conversely, good BP control slightly decreased but did not stop the progression in mean-IMT, which is likely to reflect some hypertrophy of the arterial media layer.

For a slowly varying stimulus, the simplest relationship between a neuron's input and output is a rate code, in which the spike rate is a unique function of the stimulus at that instant. In the case of spike-rate adaptation, there is no unique relationship between input and output, because the spike rate at any time depends both on the instantaneous stimulus and on prior spiking (the "history"). To improve the decoding of spike trains produced by neurons that show spike-rate adaptation, we developed a simple scheme that incorporates "history" into a rate code. We utilized this rate-history code successfully to decode spike trains produced by 1) mathematical models of a neuron in which the mechanism for adaptation (IAHP) is specified, and 2) the gastropyloric receptor (GPR2), a stretch-sensitive neuron in the stomatogastric nervous system of the crab Cancer borealis, that exhibits long-lasting adaptation of unknown origin. Moreover, when we modified the spike rate either mathematically in a model system or by applying neuromodulatory agents to the experimental system, we found that changes in the rate-history code could be related to the biophysical mechanisms responsible for altering the spiking., (Copyright © 2016 the American Physiological Society.)

Aim: Circulating osteoprogenitors and receptor activator of nuclear factor kappa-B ligand (RANKL) expression in immune cells have been implicated in the pathogenesis of osteoporosis and vascular calcification. The role played by statin therapy in the bone-vascular axis is unknown., Methods: Twenty naïve postmenopausal osteoporotic hypercholesterolemic women were treated with Atorvastatin 40 mg/day for 3 months. Gene expression analysis was performed to assess modification in osteoprotegerin (OPG)/RANK/RANKL expression in isolated T cells and monocytes. A flow cytometry analysis was used to study changes in the levels of circulating osteoprogenitor cells., Results: After 3 months of treatment, Atorvastatin significantly reduced total cholesterol and LDL-C, without affecting HDL-C and triglycerides. Among circulating bone and phosphocalcium homeostasis markers, we found a significant increase in OPG levels (P < 0.01) and a modest reduction in osteocalcin (OCN) (P < 0.05). We also observed a significant reduction in RANKL expression in T cells (P < 0.05). No differences were found in the expression of RANK in T cells and RANKL and RANK in monocytes. OPG expression was low in both immune cell types and was not affected by the treatment. As for circulating osteoprogenitors, we found a significant reduction of CD34(+) BAP(+) (P < 0.05) and CD34(+) OCN(+) BAP(+) (P < 0.05) cells. In vitro studies showed that Atorvastatin reduced RANKL expression in activated human T-lymphoblastoid cells (Jurkat cell line)., Conclusions: Three-month Atorvastatin treatment leads to a reduction in circulating osteoprogenitor cells and RANKL expression in T cells, as well as increase in OPG serum levels. These data suggest that statins could have protective effects in the bone-vascular axis., (© 2015 John Wiley & Sons Ltd.)

Background/Objectives: This study aimed to evaluate the prognostic value of preoperative neutrophil-to-lymphocyte ratio (NLR) in patients with peripheral arterial disease (PAD) undergoing femoral endarterectomy. Methods: We performed a retrospective analysis of our institutional data, evaluating consecutive patients with PAD who underwent femoral endarterectomy between January 2013 and March 2023. The main objective was to assess the prognostic value of preoperative NLR for 5-year mortality. Additionally, we examined its relationship with perioperative clinicopathological features and 5-year major adverse limb events (MALEs). Results: During the study period, 200 consecutive patients underwent femoral endarterectomy. Of these, 128 patients with available NLR values within 30 days prior to surgery were analyzed. According to the receiver operating characteristic curve, the cut-off value of NLR was 4.0. Eighty-seven patients (68.0%) were assigned to the low-NLR group, and 41 patients (32.0%) to the high-NLR group. The frequency of postoperative complications did not differ significantly between the two groups. Freedom from MALEs up to five years was significantly lower in the high-NLR group (66.0% vs. 46.5%, p = 0.006). The overall survival rates were significantly lower in the high-NLR group (p < 0.001). At 1, 3, and 5 years, the survival rates in the low-NLR group were 96.4%, 91.6%, and 84.5%, respectively, while those in the high-NLR group were 84.2%, 59.5%, and 42.5%. Univariate analysis showed that cerebrovascular disease, end-stage renal disease, Rutherford category ≥ 4, a low albumin concentration (<3.5 g/dL), and a high NLR were significantly associated with 5-year mortality. Multivariate analysis indicated that a high NLR was the only independent factor associated with 5-year mortality. Conclusions: Preoperative NLR > 4.0 was significantly associated with 5-year rates of MALE and mortality in patients with symptomatic CFA occlusive disease who underwent femoral endarterectomy. [ABSTRACT FROM AUTHOR]

The prevalence of cardiovascular disease varies with sex, and the impact of intrinsic sex-based differences on vasculature is not well understood. Animal models can provide important insights into some aspects of human biology; however, not all discoveries in animal systems translate well to humans. To explore the impact of chromosomal sex on proteomic phenotypes, we used iPSC-derived vascular smooth muscle cells from healthy donors of both sexes to identify sex-based proteomic differences and their possible effects on cardiovascular pathophysiology. Our analysis confirmed that differentiated cells have a proteomic profile more similar to healthy primary aortic smooth muscle cells than iPSCs. We also identified sex-based differences in iPSC-derived vascular smooth muscle cells in pathways related to ATP binding, glycogen metabolic process, and cadherin binding as well as multiple proteins relevant to cardiovascular pathophysiology and disease. Additionally, we explored the role of autosomal and sex chromosomes in protein regulation, identifying that proteins on autosomal chromosomes also show sex-based regulation that may affect the protein expression of proteins from autosomal chromosomes. This work supports the biological relevance of iPSC-derived vascular smooth muscle cells as a model for disease, and further exploration of the pathways identified here can lead to the discovery of sex-specific pharmacological targets for cardiovascular disease. [ABSTRACT FROM AUTHOR]

Chronological age has been the standard for quantifying the aging process. While it is simple to quantify it cannot fully discern the biological variability of aging between individuals. The growing body of interest in this variability of human aging has led to the introduction of new biomarkers to operationalize biological age. The inclusion of body composition may provide additional value to biological aging as a prediction and estimation factor of individual health outcomes. Diagnostic images based on radiomic techniques such as Computed Tomography contain an untapped wealth of patient‐specific data that remain inaccessible to healthcare providers. These images are beneficial for collecting information from body composition that adds precision and granularity when compared to traditional measures. This information can subsequently be aggregated to construct models for changes in the human body associated with aging. In addition, aging leads to a natural decline in the best parameter of drug dosing in older adults, glomerular filtration rate. Since the conventional models of kidney function are correlated with age and body composition, the radiomic biomarkers representing age‐related changes in body composition may also serve as potential new imaging biomarkers of kidney function for personalized dosing. Our review introduces potential radiomic biomarkers as measures of body composition change targeting the aging processes. As a functional example, we have hypothesized an age‐related model of radiomics as a covariate of kidney function to improve personalized dosing. Future research focusing on evaluating this hypothesis in human subject studies is acknowledged. [ABSTRACT FROM AUTHOR]

Background: Many studies have indicated that hyperuricemia is positively correlated with secondary deep venous thrombosis (DVT); however, the risk factors for idiopathic DVT based on gender differences, such as serum uric acid (SUA) and hyperuricemia, have not been fully examined. Objectives: To investigate the association between hyperuricemia and the occurrence of idiopathic lower extremity DVT based on gender differences. Methods: This was a retrospective analysis of 4299 patients who were hospitalized at the Affiliated Hospital of Qingdao University from January 2012 to October 2021 and who underwent ultrasound of the lower limbs. A total of 930 patients were diagnosed in the DVT group, and 3369 patients were diagnosed in the control group without DVT. The baseline SUA and other important baseline data were compared between the two groups, and sex was stratified. Multivariate logistic regression analysis models adjusted for potential confounders were used to investigate the associations between hyperuricemia and idiopathic lower extremity DVT. Results: The SUA level in patients with idiopathic DVT was significantly greater than that in patients without DVT (total: 6.00 ± 1.75 vs. 5.40 ± 1.56 mg/dL, respectively; male: 6.42 ± 1.60 vs. 5.87 ± 1.57 mg/dL, respectively; female: 5.58 ± 1.79 vs. 4.72 ± 1.27 mg/dL, respectively; all P < 0.001). The proportion of patients with hyperuricemia in the idiopathic DVT group was significantly greater than that in the control group (total: 29.03% vs. 16.10%, respectively; male: 35.26% vs. 23.19%, respectively; female: 22.73% vs. 5.74%, respectively; all P < 0.001). The incidence of DVT in patients with hyperuricemia was significantly greater than patients with normouricemia (33.29% vs. 18.92%, respectively), and this difference was particularly prominent among women (58.01%). According to the univariate model, hyperuricemia was significantly associated with a grester risk of idiopathic DVT. After adjustment for potential confounders, this association remained significant. The risk of idiopathic lower extremity DVT in patients with hyperuricemia was 2.643-fold greater than that in patients with normouricemia (Model 3: OR: 2.643, 95% CI: 2.165–3.228). After stratification by sex, the risk of idiopathic lower extremity DVT in female patients with hyperuricemia was 7.482-fold greater than that in patients with normouricemia (Model 3, OR: 7.482, 95% CI: 4.999–11.199). Conclusion: In the Chinese population, hyperuricemia is closely related to an increased risk of idiopathic lower extremity DVT, especially in female patients. [ABSTRACT FROM AUTHOR]

Coronary artery calcification (CAC) is a hallmark of atherosclerosis and a critical factor in the development and progression of coronary artery disease (CAD). This review aims to address the complex pathophysiological mechanisms underlying CAC and its relationship with CAD. We examine the cellular and molecular processes that drive the formation of calcified plaques, highlighting the roles of inflammation, lipid accumulation, and smooth muscle cell proliferation. Additionally, we explore the genetic and environmental factors that contribute to the heterogeneity in CAC and CAD presentation among individuals. Understanding these intricate mechanisms is essential for developing targeted therapeutic strategies and improving diagnostic accuracy. By integrating current research findings, this review provides a comprehensive overview of the pathways linking CAC to CAD, offering insights into potential interventions to mitigate the burden of these interrelated conditions. [ABSTRACT FROM AUTHOR]

The past few decades have brought tremendous insight into the molecular and pathophysiological mechanisms responsible for thrombus generation. For a clinician, it is usually sufficient to explain the incident of deep vein thrombosis (DVT) with provoking factors such as trauma with vascular injury, immobilization, hormonal factors, or inherited or acquired coagulation defects. About half of DVTs are, however, lacking such triggers and are called unprovoked. Venous stasis and hypoxia at the valve sinus level may start a chain of reactions. The concept of immunothrombosis has added a new dimension to the old etiological triad of venous stasis, vessel wall injury, and changes in blood components. This is particularly important in COVID-19, where hyperinflammation, cytokines, and neutrophil extracellular traps are associated with the formation of microthrombi in the lungs. To better understand the mechanisms behind DVT and reach beyond the above-mentioned simplifications, animal models and clinical epidemiological studies have brought insight into the complex interplay between leukocytes, platelets, endothelium, cytokines, complements, and coagulation factors and inhibitors. These pathways and the interplay will be reviewed here, as well as the roles of cancer, anticancer drugs, and congenital thrombophilic defects on the molecular level in hypercoagulability and venous thromboembolism. [ABSTRACT FROM AUTHOR]

Objectives: Pyrophosphate (PPi) is a potent inhibitor of ectopic mineralization but its role during aortic valve calcification is not known., Methods: Anti-calcific effect of PPi was investigated by using an in vitro model of serum-driven calcification of collagen sponges and decellularized porcine aortic valve leaflets. Bovine interstitial valve cells (VIC), seeded either within the collagen matrices or in transwell chambers, were used to test cellular ability to inhibit serum-induced calcification. PPi metabolism was investigated in clonal VIC harboring different calcifying potential., Results: In a cell-free system, high serum levels induced a dose-dependent calcification of type I collagen matrices which was prevented by PPi and ATP supplementation. Blockade of serum-driven calcification by PPi and ATP was also observed when using decellularized porcine aortic valve leaflets. A similar anti-calcific effect was also seen for bovine VIC, either statically seeded into the collagen matrices or co-cultured by using a transwell system. However, when we performed co-culture experiments by using clonal VIC harboring different calcifying potential, we observed that the subset of cells acquiring a pro-calcific profile lost the ability to protect the collagen from serum-driven calcification. Pro-calcific differentiation of the clonal VIC was accompanied by increase in ALP along with significant reduction in NPP activity and ATP/PPi extracellular accumulation. These changes were not observed in the clonal subtype with lower propensity towards calcification., Conclusions: We showed that PPi and ATP are potent inhibitors of serum-driven calcification of collagen matrix and that their extracellular accumulation is reduced in calcifying VIC., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Objective: To evaluate the progression of subclinical atherosclerosis in Psoriatic Arthritis (PsA) patients treated with anti-tumor necrosis factor (TNF)-α agents., Methods: Thirty-two PsA patients classified according to the CASPAR criteria and attending the Rheumatology Unit of the University of Padua Medical Center were enrolled in a two-year prospective, observational study. In accordance with the ASAS/EULAR recommendations on the management of these patients, those studied were prescribed biological agents [etanercept (n=21), adalimumab (n=6), infliximab (n=5)]. Plasma lipids, inflammatory biomarkers, including C-reactive protein (CRP), interleukin-6 (IL-6), vessel endothelium growth factor (VEGF), osteoprotegerin (OPG), and TNF-α, as well as Disease Activity Score 28 calculated with CRP (DAS 28-CRP) were evaluated at baseline and after two years of treatment. Bilateral carotid B-mode ultrasound measurements [the mean-intima media thickness (mean-IMT), the mean maximum-IMT (M-Max)] of each carotid artery segment (common, bulb, and internal carotid artery) and the post-occlusion flow-mediated dilation (FMD) of the brachial artery were also assessed at baseline and after two years., Results: Despite an improvement in the DAS 28-CRP score (P<0.0005) and lower low-density lipoprotein cholesterol (P<0.013) and triglyceride (P<0.036) values, there was a significant progression in both the mean-IMT (P<0.0005) and M-Max (P<0.0005). Moreover, no recovery in FMD (P=ns) was observed after two years of anti TNF-α treatment. Serum TNF-α levels were increased (P=0.003) and OPG values were decreased (P=0.011) at the end of follow- up with respect to baseline values., Conclusions: Despite improvement in clinical status, arterial remodelling was observed in the PsA patients who were treated with anti TNF-α agents for two years., (Copyright © 2014 Société française de rhumatologie. Published by Elsevier SAS. All rights reserved.)

The impact on cardiovascular events achieved by statin therapy seems to be mostly attributable to their cholesterol- lowering effect, with a highly debated contribution of the lipid-independent pleiotropic effects. Statins have an established role in the treatment of hypercholesterolemia with a clear and robust reduction in cardiovascular morbidity and mortality. Nevertheless, the pathophysiologic effect of statins on inflammatory responses and local atherosclerotic plaque morphology in humans remains a matter of debate. In particular, the question remains whether statin-induced alterations in plaque composition can be ascribed mainly to low density lipoprotein cholesterol (LDL-C) lowering or an antiinflammatory pleiotropic effect, or both. This review summarizes the available evidence of the effects of statins on carotid plaque cellular composition in clinical settings, focusing on lipid-related and lipid-independent effects of statin therapy. A systematic review of the web online databases was performed. Studies in humans evaluating the effect of statins on composition of carotid plaque removed at endarterectomy were eligible for inclusion. Data support the view that plaque composition even after a short-term lipid lowering therapy is significantly modulated by the degree of LDL-C lowering. A contribution of LDL-C independent, anti-inflammatory mechanisms of statins on plaque stability is only suggested by some of the studies. Actually, data strongly support the current guidelines based on progressively lower LDL-C targets depending upon the cardiovascular risk of individual patients.

The OPG/RANK/RANKL axis is now recognized as a master regulator of bone remodeling, controlling osteoclast's maturation and extracellular matrix calcification. Nevertheless, a number of clinical and basic science studies conducted in the last few years demonstrated that the triad could be also involved in several physiological and pathological processes outside the bone tissue. In particular, evidences have been collected showing an active participation of OPG and RANKL in vascular pathology, including atherogenesis and arterial calcification. A series of epidemiological studies also showed that increased circulating levels of OPG are associated with significant, independent predictive value for future cardiovascular mortality/morbidity. However, the human studies did not unravel whether OPG should be considered as a promoter, a protective mechanism or is instead neutral with regard of vascular disease progression. Main objective of the present review is to summarize findings from both in vivo and in vitro investigations on the role played by OPG in vascular disease progression and to delineate a plausible scenario on the actual involvement of the OPG/RANK/RANKL triad and TRAIL in cardiovascular pathology.

Objective: We investigated the association between cholesterol across the LDL density range and in the VLDL and IDL particles with the prevalence of inflammatory cells in plaques of patients with severe carotid artery stenosis., Methods: Forty-five patients undergoing carotid endarterectomy were studied. Plaque specimens were analyzed for cellular composition by immunocytochemistry using monoclonal antibodies. Lipoprotein subclasses were separated by gradient ultracentrifugation., Results: We found no correlations between LDL-C, HDL-C and plasma triglyceride levels with plaque cellular composition. On the other hand, macrophage content was significantly related to cholesterol in the dense LDL subclasses (r = 0.30, p < 0.01) and in the triglyceride-rich lipoprotein remnants, namely dense VLDL and IDL particles (r = 0.46, p < 0.01). HDL subclasses were not correlated with plaque cellular composition. In a mirror manner, smooth muscle cells were inversely associated with cholesterol levels of the dense LDL subclasses (r = -0.32, p < 0.01 fraction 10; r = -0.26, p < 0.05 fraction 11) while only a non-significant trend was observed with the cholesterol in the VLDL-IDL fractions. These results provide the pathophysiological background to account for the relevance of non-HDL-C as the only lipid parameter, aside LDL density, significantly associated (β = 0.351, p = 0.021) with carotid plaque macrophage content., Conclusions: We provide evidence that lipoprotein subclasses, specifically cholesterol in the dense LDL fractions and in the triglyceride-rich lipoprotein remnants, significantly affect carotid plaque cellular composition, in particular macrophages content., (© 2013 Elsevier Ireland Ltd. All rights reserved.)

The relationship between MetS (metabolic syndrome), levels of circulating progenitor/immune cells and the risk of VTE (venous thromboembolism) has not yet been investigated. We studied 240 patients with previous VTE and 240 controls. The presence of MetS was identified according to NCEP ATP III guidelines and flow cytometry was used to quantify circulating CD34(+) cells. VTE patients showed higher BMI (body mass index), waist circumference, triacylglycerol (triglyceride) levels, blood glucose, hs-CRP (high-sensitivity C-reactive protein) and lower HDL-C (high-density lipoprotein cholesterol) levels. The prevalence of MetS was significantly higher in VTE (38.3%) than in control individuals (21.3%) with an adjusted OR (odds ratio) for VTE of 1.96 (P=0.002). VTE patients had higher circulating neutrophils (P<0.0001), while the CD34(+) cell count was significantly lower among patients with unprovoked VTE compared with both provoked VTE (P=0.004) and controls (P=0.003). Subjects were also grouped according to the presence/absence of MetS (MetS(+) or MetS(-)) and the level (high/low) of both CD34(+) cells and neutrophils. Very high adjusted ORs for VTE were observed among neutrophils&#95;high/MetS(+) (OR, 3.58; P<0.0001) and CD34(+)&#95;low/MetS(+) (OR, 3.98; P<0.0001) subjects as compared with the neutrophils&#95;low/MetS(-) and CD34(+)&#95;high/MetS(-) groups respectively. In conclusion, low CD34(+) blood cell count and high circulating neutrophils interplay with MetS in raising the risk for venous thromboembolic events.

It is now well established that hypertension is accompanied by remodeling of the arterial wall with significant modifications in extracellular matrix composition and in vascular cell phenotype. Some of these changes, particularly elastin fragments generation, increased proteases activity and activation of transforming growth factor-β signaling together with deposition of collagen and proteoglycans might generate a permissive soil for vascular calcification. On the other hand, calcium deposits within large arterial conduits can reduce vessel's elasticity and contribute to the generation of blood pressure pattern associated with vascular stiffness, namely isolated systolic hypertension. Hence, a hypothetical vicious cycle exists between hypertensive arterial damage and vascular calcification. Herein, we revised clinical and basic science findings supporting this possibility.

Objective: To evaluate the effect of a continuous infusion of basic fibroblast growth factor on the adaptive potential of the right ventricular myocardium after 30 days of mechanically induced overload in rats. Materials and methods We banded the pulmonary trunk, so as to increase the systolic workload of the right ventricle, in six Lewis/HanHsd rats at the age of 11 weeks, using six adult rats as controls. The six adult rats were also banded and received an additional continuous infusion of basic fibroblastic growth factor, using six rats with a continuous infusion of basic fibroblastic growth factor only as controls. We analysed the functional adaptation and structural changes of the right ventricular myocardium, blood vessels, and interstitial tissue 30 days after the increased afterload., Results: The pulmonary artery banding induced an increase in the right ventricular free wall thickness of banded rats when compared with controls, which was mainly justified by an increase in cardiomyocyte area and in the percentage of extracellular fibrosis. The infusion of basic fibroblastic growth factor promotes a more extensive capillary network in banded rats (p < 0.001), which modulates the compensatory response of the right ventricle, promoting the hypertrophy of contractile elements and limiting the areas in which fibrosis develops (p < 0.001)., Conclusions: The subcutaneous infusion with osmotic pumps was a valid and reproducible method of delivering basic fibroblast growth factor to heart tissue. This infusion contributed to better preserve the right ventricular capillary network, hampering the development of interstitial fibrosis.

Calcification of arteries and cardiac valves is observed commonly in dialysis patients and represents a major determinant of the heightened cardiovascular risk observed during chronic kidney disease (CKD) progression. Recent advances from clinical and basic science studies suggest that vascular calcification should be considered a systemic disease in which pathologic processes occurring in the bone and kidney contribute to calcium deposition in the vasculature. Among the factors potentially involved in the vascular-bone axis dysregulation associated with CKD, there now is increasing interest in the role of the phosphaturic hormone fibroblast growth factor 23 (FGF-23). Increased FGF-23 plasma levels are observed with a decrease in kidney function and predict the risk of future cardiovascular mortality. However, clinical data are still unclear about whether a direct pathogenetic effect of FGF-23 on vascular/kidney/bone health exists. In the last few years, a series of basic science studies, performed using engineered mice, have contributed important pathophysiologic information about FGF-23 activities. This review summarizes findings from these studies and discusses the potential role of FGF-23 during the pathologic interplay between kidney, vessels, and bone in CKD., (Copyright © 2011 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Patients treated with amiodarone accumulate lysobisphosphatidic acid (LBPA), also known as bis(monoacylglycero)phosphate, in airway secretions and develop in different tissues vacuoles and inclusion bodies thought to originate from endosomes. To clarify the origin of these changes, we studied in vitro the effects of amiodarone on endosomal activities like transferrin recycling, Shiga toxin processing, ESCRT-dependent lentivirus budding, fluid phase endocytosis, proteolysis and exosome secretion. Furthermore, since the accumulation of LBPA might point to a broader disturbance in lipid homeostasis, we studied the effect of amiodarone on the distribution of LBPA, unesterified cholesterol, sphingomyelin and glycosphyngolipids. Amiodarone analogues were also studied, including the recently developed derivative dronedarone. We found that amiodarone does not affect early endosomal activities, like transferrin recycling, Shiga toxin processing and lentivirus budding. Amiodarone, instead, interferes with late compartments of the endocytic pathway, blocking the progression of fluid phase endocytosis and causing fusion of organelles, collapse of lumenal structures, accumulation of undegraded substrates and amassing of different types of lipids. Not all late endocytic compartments are affected, since exosome secretion is spared. These changes recall the Niemann-Pick type-C phenotype (NPC), but originate by a different mechanism, since, differently from NPC, they are not alleviated by cholesterol removal. Studies with analogues indicate that basic pKa and high water-solubility at acidic pH are crucial requirements for the interference with late endosomes/lysosomes and that, in this respect, dronedarone is at least as potent as amiodarone. These findings may have relevance in fields unrelated to rhythm control., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Calcific degeneration represents the most frequent aortic valve disease observed in industrialized countries. Our aim is to study modifications in the cytosolic and membrane protein profile of aortic interstitial valve cells (VIC) acquiring a pro-calcific phenotype. We studied a clonal population of bovine VIC that expresses bone-related proteins (such as alkaline phosphatase [ALP]) and calcifies a collagen matrix in response to endotoxin (LPS) treatment. A proteomic analysis was performed on proteins extracted from cells treated for 12 days with LPS (100 ng/mL) versus control. We identified 34 unique cytosolic and 10 unique membrane-associated proteins showing significant changes after treatment. These proteins are involved in several cellular functions, such as chaperone-mediated protein folding, protein metabolism and transport, cell redox/nitric oxide homeostasis, and cytoskeletal organization. Reduced expression of proteins involved in NOS bioactivity (such as DDAH-1 and -2) suggested a role for the l-arginine/ADMA ratio in controlling VIC phenotypic profile. In accordance with this hypothesis, we observed that exposure of clonal cells to l-arginine prevented LPS-induced ALP expression and collagen calcification. In conclusion, we identified several proteins involved in structural, metabolic, and signaling functions that are significantly altered in aortic VIC acquiring a pro-calcific profile, thus giving new insights into the pathogenesis of aortic valve degeneration.

Objective: Our purpose was to study in vitro whether phenotypically-distinct interstitial cell clones from bovine aortic valve (BVIC) possess different calcifying potential in response to endotoxin (lipopolysaccharide [LPS]) and phosphate (Pi)., Methods and Results: Among various clones of BVIC obtained by limited dilution technique we selected 4 clones displaying different growth patterns and immunophenotypes. Uncloned and cloned cells were treated with combinations of LPS (100 ng/mL) and Pi (2.4 mmol/L). Uncloned BVIC showed increased alkaline phosphatase activity (ALP) after treatment with LPS, which resulted in calcification after addition of Pi. Among BVIC clones, only Clone 1 (fibroblast-like phenotype) showed a relevant increase in ALP after LPS treatment in parallel with prevention of smooth muscle (SM) alpha-actin accumulation. No effect was observed in clonal cells harboring a more stable SM cell-like profile (Clone 4). None of the isolated clones calcified but mineralization was induced in the presence of LPS plus Pi when Clone 1 was cocultured with Clone 4 or after seeding on type I collagen sponges., Conclusions: Endotoxin and phosphate can act as valve calcification promoters by targeting specific fibroblast-like interstitial valve cells that possess a unique procalcific potential.

Background: Metabolic syndrome (MetS), characterized by central obesity, insulin resistance, dyslipidemia, and hypertension, affects 20-25% of the global population. The creatinine-to-cystatin C ratio (CCR) is an indicator of skeletal muscle mass. While CCR may play a role in MetS development, sex differences in these associations are not fully understood. Therefore, this study aimed to investigate how CCR levels are associated with MetS in a Chinese adult population, focusing on possible sex disparities. Method: We conducted a retrospective cross-sectional analysis of 9,376 adults from Xiamen Chang Gung Hospital between 2014 to 2016. We examined the relationship between CCR and MetS, adjusting for cardiometabolic risk factors. Results: The prevalence of MetS was 24.7% in males and 18.0% in females. Interestingly, we observed significant sex differences in the association between CCR quartiles and MetS. Females in the lowest CCR quartile had a significantly higher risk of MetS (odds ratio=1.84). Receiver operating characteristic curve analysis revealed acceptable diagnostic power of CCR for MetS in females (area under the curve=0.65) but not in males. Conclusion: Our findings suggest that CCR is an independent risk factor for MetS in females, highlighting the importance of sex-specific assessments when evaluating MetS risk. [ABSTRACT FROM AUTHOR]

Background/Objectives: Neutrophils, as the first line of defense in the immune response, produce neutrophil extracellular traps (NETs) upon activation, which are significant in the pathogenesis and organ damage in sepsis. This study aims to explore the clinical value of myeloperoxidase-DNA (MPO-DNA) and cell-free DNA (cf-DNA) in sepsis patients. Methods: Clinical data were collected from 106 sepsis patients, 25 non-sepsis patients, and 51 healthy controls. Sequential Organ Failure Assessment (SOFA) scores were calculated, and levels of MPO-DNA) complexes and cf-DNA were measured using specific kits. Correlation analyses assessed relationships between indicators, while logistic regression identified independent risk factors. Receiver operating characteristic (ROC) curves calculated the area under the curve (AUC) to evaluate the diagnostic value of the biomarkers. Results: Sepsis patients exhibited significantly elevated levels of MPO-DNA and cf-DNA compared to non-sepsis patients and healthy controls. In sepsis patients, MPO-DNA and cf-DNA levels correlated with inflammation, coagulation, and organ damage indicators, as well as procalcitonin (PCT) levels and SOFA scores. Both C-reactive protein (CRP) and cf-DNA were identified as independent risk factors for sepsis, demonstrating moderate diagnostic value. ROC analysis showed that the combination of MPO-DNA and CRP (AUC: 0.837) enhances the AUC value of CRP (0.777). Conclusions: In summary, elevated serum levels of MPO-DNA and cf-DNA in sepsis patients correlate with SOFA scores and PCT levels, providing reference value for sepsis diagnosis in clinical settings. [ABSTRACT FROM AUTHOR]

Diabetic macroangiopathy is a leading cause of diabetes-related mortality worldwide. Both genetic and environmental factors, through a multitude of underlying molecular mechanisms, contribute to the pathogenesis of diabetic macroangiopathy. MicroRNAs (miRNAs), a class of non-coding RNAs known for their functional diversity and expression specificity, are increasingly recognized for their roles in the initiation and progression of diabetes and diabetic macroangiopathy. In this review, we will describe the biogenesis of miRNAs, and summarize their functions in diabetic macroangiopathy, including atherosclerosis, peripheral artery disease, coronary artery disease, and cerebrovascular disease, which are anticipated to provide new insights into future perspectives of miRNAs in basic, translational and clinical research, ultimately advancing the diagnosis, prevention, and treatment of diabetic macroangiopathy. [ABSTRACT FROM AUTHOR]

Background/Objectives: This study compares the power of the radiofrequency (RF) signal reflected from the media layer (media power) of the common carotid artery (CCA) and the CCA stiffness between individuals with and without type 2 diabetes mellitus (T2DM). It also evaluates the associations of CCA media power with plasma glucose and lipid levels, as well as carotid stiffness. Methods: A total of 540 individuals, 115 with and 425 without T2DM (273 males, mean age = 64 ± 8 years) were studied using RF-based tracking of the right CCA. The following parameters were measured: CCA media thickness, luminal diameter, wall tensile stress (WTS), local pulse wave velocity (PWV), and media power. Results: Compared to the non-diabetic individuals, the T2DM patients had significantly higher CCA media thickness (652 ± 122 vs. 721 ± 138 microns, p < 0.005), luminal diameter (6.12 ± 0.78 vs. 6.86 ± 0.96 mm, p < 0.0005), media power (36.1 ± 4.8 vs. 39.3 ± 4.6, p < 0.0001), and PWV (7.65 ± 1.32 vs. 8.40 ± 1.89 m/s; p < 0.01), but comparable WTS (32.7 ± 10.4 vs. 33.1 ± 10.7 kPa; p = 0.25). In the entire population, CCA media power was independently associated with male sex, pulse pressure, current smoking, and T2DM; when T2DM was not included in the model, triglycerides emerged as an independent determinant of media power. The CCA PWV was independently associated with age, pulse pressure, media power, and T2DM. Conclusions: Our findings suggest the presence of structural changes in the arterial media of T2DM patients, leading to carotid stiffening and remodeling, aiming to preserve WTS. T2DM-related changes in arterial wall composition may be driven by high plasma triglyceride levels, which have previously been associated with both arterial stiffening and the incidence of CV events. [ABSTRACT FROM AUTHOR]

Background: Since 2015, the pulmonary artery banding (PAB), following the Giessen protocol, has treated end-stage heart failure in selected infants with preserved right ventricular function, acting as a bridge to transplant or recovery, as a result of ventricular-ventricular interaction. Objectives: To elucidate whether PAB is a feasible and reproducible procedure in a rodent model of pharmacologically induced dilated cardiomyopathy (DCM) and to evaluate PAB-induced ventricular rehabilitation. Methods: We used 49 Sprague-Dawley rats divided into four groups: a sham surgery control group, a healthy animal group undergoing PAB, a doxorubicin (DOX)- treated control group, and a DOX + PAB-treated group. All underwent echocardiographic, histological, and molecular analyses. Results: Preliminary results showed high mortality in rats with DOX-induced DCM, with contractile dysfunction confirmed by 2D echocardiography. Signs of damage were detected through transmission electron microscopy, but not via standard histological/molecular tests. PAB after DOX improved contractile function, enhancing ejection fraction (p = 0.01) and fractional shortening (p = 0.03). Conclusion: The DOX-induced DCM model, while reproducible, may not reflect DCM's true pathology. High mortality and individual variability limited the study. Further research is needed to find alternative models with lower mortality and to explore the PAB-induced molecular signaling pathways and cardiac proliferation potential. [ABSTRACT FROM AUTHOR]

Cardiovascular calcification, characterized by hydroxyapatite deposition in the arterial wall and heart valves, is associated with high cardiovascular morbidity and mortality. Cardiovascular calcification is a hallmark of aging but is frequently seen in association with chronic diseases, such as chronic kidney disease (CKD), diabetes, dyslipidemia, and hypertension in the younger population as well. Currently, there is no therapeutic approach to prevent or cure cardiovascular calcification. The pathophysiology of cardiovascular calcification is highly complex and involves osteogenic differentiation of various cell types of the cardiovascular system, such as vascular smooth muscle cells and valve interstitial cells. In vitro cellular and ex vivo tissue culture models are simple and useful tools in cardiovascular calcification research. These models contributed largely to the discoveries of the numerous calcification inducers, inhibitors, and molecular mechanisms. In this review, we provide an overview of the in vitro cell culture and the ex vivo tissue culture models applied in the research of cardiovascular calcification. [ABSTRACT FROM AUTHOR]

The number of patients with end-stage renal disease (ESRD) requiring hemodialysis is increasing worldwide. Although arteriovenous fistula (AVF) is the best and most important vascular access (VA) for hemodialysis, its primary maturation failure rate is as high as 60%, which seriously endangers the prognosis of hemodialysis patients. After AVF establishment, the venous outflow tract undergoes hemodynamic changes, which are translated into intracellular signaling pathway cascades, resulting in an outward and inward remodeling of the vessel wall. Outward remodeling refers to the thickening of the vessel wall and the dilation of the lumen to accommodate the high blood flow in the AVF, while inward remodeling is mainly characterized by intimal hyperplasia. More and more studies have shown that the two types of remodeling are closely related in the occurrence and development of, and jointly determining the final fate of, AVF. Therefore, it is essential to investigate the underlying mechanisms involved in outward and inward remodeling for identifying the key targets in alleviating AVF dysfunction. In this review, we summarize the current clinical diagnosis, monitoring, and treatment techniques for AVF dysfunction and discuss the possible pathological mechanisms related to improper outward and inward remodeling in AVF dysfunction, as well as summarize the similarities and differences between the two remodeling types in molecular mechanisms. Finally, the representative therapeutic targets of potential clinical values are summarized. [ABSTRACT FROM AUTHOR]

Background: The common -514 C-T promoter polymorphism of the hepatic lipase gene (LIPC) and the cholesteryl ester transfer protein (CETP) gene TaqIB polymorphism affect atherogenesis. We investigated the potential relationship between these polymorphisms and the maximum-intima-media thickness (M-IMT) after carotid endarterectomy., Methods: The LIPC and CETP genotypes were determined by PCR in 68 patients undergoing endarterectomy. Plaque specimens were analysed for cell composition by immunocytochemistry. Six month after surgery the M-IMT of the revascularized vessel was assessed by B-mode ultrasonography., Results: The CC carriers had denser LDL particles (p<0.0005), an abundance of macrophages (p<0.0005), fewer SMCs in the carotid plaque (p<0.0005), and higher prevalence of cerebrovascular events (72% versus 28%, p=0.002) compared to CT/TT carriers. After endarterectomy, CC carriers showed a lower M-IMT than the CT/TT group (1.36 mm versus 1.76 mm, p=0.04). No association between the CETP polymorphism and either carotid plaque cellular composition or M-IMT was observed. In a multivariate analysis, M-IMT was associated with plaque cell composition (macrophages, r=-0.39; SMC, r=0.44; p<0.005 for both) but not with pre-operative LDL-C, HDL-C, triglycerides, or LDL density., Conclusions: The LIPC promoter -514 C-T polymorphism is associated with a significantly reduced development of neointima after surgery. This effect seems to be mediated by scarcity of SMC in the plaque of CC carriers who display an excess prevalence of cerebrovascular events prior endarterectomy but are at low risk for restenosis. The pre-operative lipid phenotype plays a marginal role in the neointima formation.

Significant structural and functional changes in smooth muscle cells (SMCs) of microvessels (diameter 30 to 300 microm) occur in hypertension. However, in microvessels of hypertensive patients, the differentiation pattern of SMCs underlying such changes remains undefined. To analyze the differentiation pattern of SMCs (adult, postnatal, or fetal), 49 muscle biopsies (rectus abdominis) were analyzed: 16 from children (aged 11 months to 11 years), 15 from normotensive adults (aged 55 to 74 years), 18 from hypertensive adults (aged 55 to 74 years). Transverse cryosections of specimens were studied by immunocytochemistry using monoclonal antibodies SM-E7 and NM-F6, which recognize smooth muscle myosin heavy chain (MyHC) and A(pla1)-like nonmuscle MyHC, respectively. The total number of microvessels was assessed via SM-E7 staining. The number of NM-F6 positive (fetal-type SMC) or negative (adult-type SMC) microvessels was assessed. The number of microvessels per area unit was considerably lower (P<0.0005) in normotensive adults (0.22+/-0.17) than in children (0.98+/-0.61). Even more significant reduction was found in hypertensive adults compared with control adults (P=0.013) and children (P<0.0005). The qualitative immunocytochemistry analysis by NM-F6 revealed 2 differentiation patterns of the media layer of microvessels: positive or negative. In hypertensive subjects, the percentage of microvessels positive to NM-F6 was 49.8+/-35.6%, close to that found in children (50.6+/-12.6%), whereas in normotensive subjects it was significantly lower (24.4+/-21.1%). The following conclusions were drawn. (1) The medial layer of microvessels is heterogeneous in terms of SMC differentiation. (2) In hypertension, a prevalence of fetal-type SMCs takes place in microvessels, resembling that of children. Compared with children, a rarefaction of microvessels is present in normotensive adults that is even more remarkable in hypertensive adults.

Over the last two decades, several studies have reported a high prevalence of cardiovascular disease in patients with end-stage renal disease (ESRD). This population usually presents both the traditional and non-traditional risk factors for atherosclerosis. Inflammation as well as impaired nitric oxide production are pivotal, throughout the whole process of development of atherosclerotic lesions from the very start. C-reactive protein (CRP), a marker of systemic inflammation and an independent predictor of cardiovascular mortality in the general population, and asymmetric dimethylarginine (ADMA), an endogenous inhibitor of NO synthase, are important risk factors for cardiovascular disease and mortality in the ESRD population. Increased CRP levels have been described in hemo-dialysis and peritoneal dialysis patients, probably due to concomitant diseases, recurrent infections and chronic dialytic therapy. CRP levels, however, are elevated even in predialysis patients, implying that factors related to uremia per se can promote CRP synthesis. Recent reports raise the question whether CRP could be more than just a sensitive marker of inflammation and may contribute actively to the development of the atherosclerotic lesion. ADMA accumulation in the ESRD population is a consequence of reduced renal excretion and impaired enzymatic degradation and is related to the progression of atherosclerosis. Both CRP and ADMA have been shown to be associated with increases in the incidence and progression of atherosclerotic lesions in carotid arteries, as evaluated by high-resolution Doppler ultrasonography.

Objective: We investigated the potential association between -514 C-->T polymorphism in the promoter of the hepatic lipase gene (LIPC) and the prevalence of inflammatory cells in the plaque of patients with severe carotid artery stenosis., Background: This common LIPC polymorphism has been related to the presence of an atherogenic lipoprotein pattern., Methods: We studied 68 consecutive patients undergoing carotid endarterectomy. The LIPC genotype was determined by polymerase chain reaction. Endarterectomy specimens were examined by immunocytochemistry using monoclonal antibodies for smooth muscle cells, macrophages, or lymphocytes., Results: In 50 of 68 patients who had evidence of previous ipsilateral ischemic events, 36 (72%) were carriers of the CC genotype, whereas only 14 (28%) were carriers of the CT/TT genotype (p = 0.002). Among the 18 patients without evidence of events, the two genotypes were equally distributed (9 vs. 9). The low-density lipoprotein (LDL) particles were denser in CC than in CT/TT genotype carriers (flotation rate: 0.315 +/- 0.025 vs. 0.356 +/- 0.019, p < 0.0005). The CC genotype was associated with an abundance of macrophages (6.7 +/- 3.5 vs. 2.1 +/- 2.1 cells/area unit in the CT/TT group, p < 0.0005) and a reduced number of smooth muscle cells (6.9 +/- 6.2 vs. 14.5 +/- 6.4 in the CT/TT group, p < 0.0005) in the plaque. An inverse relationship was found between LDL buoyancy and the number of macrophages in the plaque (r = -0.639, p < 0.0005)., Conclusion: We provide evidence, for the first time, that LIPC promoter -514 C-->T polymorphism, by modulating LDL density, significantly affects the number of macrophages in the plaque and possibly affects the occurrence of cerebrovascular events in patients with carotid artery stenosis.

The adventitial layer surrounding the blood vessels has long been exclusively considered a supporting tissue the main function of which is to provide adequate nourishment to the muscle layers of tunica media. Although functionally interconnected, the adventitial and medial layers are structurally interfaced at the external elastic lamina level, clearly distinguishable at the maturational phase of vascular morphogenesis. Over the last few years the "passive" role that the adventitia seemed to play in experimental and spontaneous vascular pathologies involving proliferation, migration, differentiation, and apoptosis of vascular smooth muscle cells (VSMCs) has been questioned. It has been demonstrated that fibroblasts from the adventitia display an important partnership with the resident medial VSMCs in terms of phenotypic conversion, proliferation, apoptotic, and migratory properties the result of which is neointima formation and vascular remodeling. This article is an attempt at reviewing the major themes and more recent findings dealing with the phenotypic conversion process that leads adventitial "passive" (static) fibroblasts to become "activated" (mobile) myofibroblasts. This event shows some facets in common with vascular morphogenesis, ie, the process of recruitment, incorporation, and phenotypic conversion of cells surrounding the primitive endothelial tube in the definitive vessel wall. We hypothesize that during the response to vascular injuries in the adult, "activation" of adventitial fibroblasts is, at least in part, reminiscent of a developmental program that also invests, although with distinct spatiotemporal features, medial VSMCs.