Sequential Stem Cell-Kidney Transplantation in Schimke Immuno-osseous Dysplasia.

Lifelong immunosuppression is required for allograft survival after kidney transplantation but may not ultimately prevent allograft loss resulting from chronic rejection. We developed an approach that attempts to abrogate immune rejection and the need for post-transplantation immunosuppression in three patients with Schimke immuno-osseous dysplasia who had both T-cell immunodeficiency and renal failure. Each patient received sequential transplants of αß T-cell-depleted and CD19 B-cell-depleted haploidentical hematopoietic stem cells and a kidney from the same donor. Full donor hematopoietic chimerism and functional ex vivo T-cell tolerance was achieved, and the patients continued to have normal renal function without immunosuppression at 22 to 34 months after kidney transplantation. (Funded by the Kruzn for a Kure Foundation.).

Concentric ballooned catheterization to the fractional non-newtonian hybrid nano blood flow through a stenosed aneurysmal artery with heat transfer.

The current work analyzes the effects of concentric ballooned catheterization and heat transfer on the hybrid nano blood flow through diseased arterial segment having both stenosis and aneurysm along its boundary. A fractional second-grade fluid model is considered which describes the non-Newtonian characteristics of the blood. Governing equations are linearized under mild stenosis and mild aneurysm assumptions. Precise articulations for various important flow characteristics such as heat transfer, hemodynamic velocity, wall shear stress, and resistance impedance are attained. Graphical portrayals for the impact of the significant parameters on the flow attributes have been devised. The streamlines of blood flow have been examined as well. The present finding is useful for drug conveyance system and biomedicines.

Tratamiento endovascular de la enfermedad obstructiva aortoilíaca / Endovascular management of aortoiliac occlusive disease

Resumen Introducción: La angioplastia transluminal percutánea (ATP), se ha convertido en una técnica aceptada, en el tratamiento de la enfermedad obstrutiva aortoilíaca, con tasas de éxito del 90-92% y permeabilidad primaria del 55-72% a 5 años. Objetivo: Evaluar los resultados del tratamiento endovascular del sector aortoilíaco. Material y Método: Estudio descriptivo, retrospectivo (revisión de serie de casos unicéntrica), de pacientes, sometidos consecutivamente al tratamiento endovascular (ATP simple y ATP con stent) de la patología obstructiva del sector aortoilíaco, durante un período de 7 años (2002-2019), en el Hospital Dr. Eduardo Pereira de Valparaíso, Chile. Resultados: Se realizaron 103 procedimientos en 94 pacientes, sexo masculino: 63,83%, femenino: 36,17%, edad promedio: 67,4 años (rango 47-96), distribución de las lesiones según la clasificación TASC II: A (46,24%), B (39,78%), C (8,60%), D (5,38%), remodelando la biburfaccción aórtica (kissing stent) en un 6,80%, procedimientos híbridos (12,62%), seguimiento promedio (47,13 meses), éxito clínico (90,29%), exito técnico (94,17%), permeabilidad primaria, primaria asistida y secundaria a 5 años del 68,09%, 75,53% y 81,91% respectivamente, tasa de salvación de la extremidad a 5 años del 84,04%, mortalidad < 30 días del 1,94%, supervivencia a 5 años del 90,42%. Discusión: Las técnicas endovasculares del sector aortoilíaco son fiables, sus resultados ténicos y permeabilidad, están influenciados por el estadio clínico del paciente y severidad de las lesiones tratadas. Conclusión: En pacientes adecuadamente seleccionados, el tratamiento endovascular del sector aortoilíaco presenta excelentes resultados, permitiendo aumentar la indicación de tratamiento en pacientes considerados de alto riesgo.

Introduction: Percutaneous transluminal angioplasty (PTA) has become an accepted technique in the treatment of aortoiliac occlusive disease, with success rates of 90-92%, and primary patency of 55-72% at 5 years. Aim: To evaluate the results of endovascular treatment (PTA or PTA with stents) of the aortoiliac sector. Material and Method: Descriptive, retrospective study (single-center case series) of patients, consecutively subjected to endovascular treatment (PTA or PTA with stents) of aortoiliac occlusive disease, during a period of 7 years (2002 - 2019), at the Dr. Eduardo Pereira Hospital in Valparaíso, Chile. Results: 103 procedures were performed in 94 patients, male: 63.83%, female: 36.17%, mean age: 67.4 years (range 47-96), distribution of the lesions according to the TASC II classification: A (46.24%), B (39.78%), C (8.60%), D (5.38%), remodeling the aortic bifaction (kissing stent) in 6.80%, hybrid procedures (12.62%), average follow-up (47.13 months), clinical success (90.29%), technical success (94.17%), primary patency, assisted primary and secondary at 5 years of 68.09%, 75, 53% and 81.91% respectively, 5-year limb salvage rate of 84.04%, mortality < 30 days of 1.94%, 5-year survival of 90.42%. Discussion: Endovascular techniques in the aortoiliac sector are reliable, their technical results and patency are influenced by the clinical stage of the patient and the severity of the lesions treated. Conclusion: In appropriately selected patients, endovascular treatment of the aortoiliac sector, presents excellent results, allowing an increase in the indication for treatment in patients considered to be at high risk.

Autologous adipose mesenchymal stem cell administration in arteriosclerosis and potential for anti-aging application: a retrospective cohort study.

OBJECTIVE: Arteriosclerosis is an age-related disease and a leading cause of cardiovascular disease. In animal experiments, mesenchymal stem cells and its culture-conditioned medium have been shown to be promising tools for prevention or treatment of arteriosclerosis. On the basis of these evidences, we aimed to assess whether administration of autologous adipose-derived mesenchymal stem cells (Ad-MSC) is safe and effective for treatment of arteriosclerosis. METHODS: We retrospectively reviewed clinical records of patients with arteriosclerosis who had received autologous Ad-MSC administration at our clinic. Patients' characteristics were recorded and data on lipid profile, intimal-media thickness (IMT), cardio-ankle vascular index (CAVI), and ankle-brachial index (ABI) before and after Ad-MSC administration were collected and compared. RESULTS: Treatment with Ad-MSC significantly improved HDL, LDL, and remnant-like particle (RLP) cholesterol levels. No adverse effect or toxicity was observed in relation to the treatment. Of the patients with abnormal HDL values before treatment, the vast majority showed improvement in the values. Overall, the measurements after treatment were significantly increased compared with those before treatment (p < 0.01). In addition, decreases in LDL cholesterol and RLP levels were observed after treatment in patients who had abnormal LDL cholesterol or RLP levels before treatment. The majority of patients with pre-treatment abnormal CAVI values had improved values after treatment. In patients with available IMT values, a significant decrease in the IMT values was found after therapy (p < 0.01). All patients with borderline arteriosclerosis disease had improved laboratory findings after treatment. In general, post-treatment values were significantly decreased as compared with pre-treatment values. Of the patients with normal ABI values before treatment at the same time as CAVI, the vast majority remained normal after treatment. CONCLUSIONS: These findings suggest that Ad-MSC administration is safe and effective in patients developing arteriosclerosis, thereby providing an attractive tool for anti-aging application.

[What's new in CKD-MBD?] / CKD-MBD: Was gibt es Neues?

CKD-MBD (chronic kidney disease - mineral and bone disorder) describes a complex syndrome of renal osteodystrophy, mineral disturbances and cardiovascular disease in patients with chronic kidney disease. The present articles intends to provide an up-to-date summary of recent clinically important developments in the field of CKD-MBD. The article touches specifically phosphate management, secondary hyperparathyroidism, vitamin D, arteriosclerosis, renal bone disease, and SGLT2-inhibitors. The summary also comments on which grade of evidence novel aspects and innovative developments in CKD-BMD are based. The author concludes that nephrologists should strive after more high-quality, large-scale randomized-controlled interventional trials in order to optimize the evidence behind CKD-MBD therapy.

Chelation therapy for atherosclerotic cardiovascular disease.

BACKGROUND: Chelation therapy is promoted and practiced around the world as a form of alternative medicine in the treatment of atherosclerotic cardiovascular disease. It has been suggested as a safe, relatively inexpensive, non-surgical method of restoring blood flow in atherosclerotic vessels. However, there is currently limited high-quality, adequately-powered research informing evidence-based medicine on the topic, specifically regarding clinical outcomes. Due to this limited evidence, the benefit of chelation therapy remains controversial at present. This is an update of a review first published in 2002. OBJECTIVES: To assess the effects of ethylene diamine tetra-acetic acid (EDTA) chelation therapy versus placebo or no treatment on clinical outcomes among people with atherosclerotic cardiovascular disease. SEARCH METHODS: For this update, the Cochrane Vascular Information Specialist searched the Cochrane Vascular Specialised Register, Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase and Cumulative Index to Nursing and Allied Health Literature (CINAHL) databases, the World Health Organization International Clinical Trials Registry Platform and ClinicalTrials.gov trials register to 6 August 2019. We searched the bibliographies of the studies retrieved by the literature searches for further trials. SELECTION CRITERIA: We included studies if they were randomised controlled trials of EDTA chelation therapy versus placebo or no treatment in participants with atherosclerotic cardiovascular disease. The main outcome measures we considered include all-cause or cause-specific mortality, non-fatal cardiovascular events, direct or indirect measurement of disease severity, and subjective measures of improvement or adverse events. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data and assessed trial quality using standard Cochrane procedures. A third author considered any unresolved issues, and we discussed any discrepancies until a consensus was reached. We contacted study authors for additional information. MAIN RESULTS: We included five studies with a total of 1993 randomised participants. Three studies enrolled participants with peripheral vascular disease and two studies included participants with coronary artery disease, one of which specifically recruited people who had had a myocardial infarction. The number of participants in each study varied widely (from 10 to 1708 participants), but all studies compared EDTA chelation to a placebo. Risk of bias for the included studies was generally moderate to low, but one study had high risk of bias because the study investigators broke their randomisation code halfway through the study and rolled the placebo participants over to active treatment. Certainty of the evidence, as assessed by GRADE, was generally low to very low, which was mostly due to a paucity of data in each outcome's meta-analysis. This limited our ability to draw any strong conclusions. We also had concerns about one study's risk of bias regarding blinding and outcome assessment that may have biased the results. Two studies with coronary artery disease participants reported no evidence of a difference in all-cause mortality between chelation therapy and placebo (risk ratio (RR) 0.97, 95% CI 0.73 to 1.28; 1792 participants; low-certainty). One study with coronary artery disease participants reported no evidence of a difference in coronary heart disease deaths between chelation therapy and placebo (RR 1.02, 95% CI 0.70 to 1.48; 1708 participants; very low-certainty). Two studies with coronary artery disease participants reported no evidence of a difference in myocardial infarction (RR 0.81, 95% CI 0.57 to 1.14; 1792 participants; moderate-certainty), angina (RR 0.95, 95% CI 0.55 to 1.67; 1792 participants; very low-certainty), and coronary revascularisation (RR 0.46, 95% CI 0.07 to 3.25; 1792 participants). Two studies (one with coronary artery disease participants and one with peripheral vascular disease participants) reported no evidence of a difference in stroke (RR 0.88, 95% CI 0.40 to 1.92; 1867 participants; low-certainty). Ankle-brachial pressure index (ABPI; also known as ankle brachial index) was measured in three studies, all including participants with peripheral vascular disease; two studies found no evidence of a difference in the treatment groups after three months after treatment (mean difference (MD) 0.02, 95% CI -0.03 to 0.06; 181 participants; low-certainty). A third study reported an improvement in ABPI in the EDTA chelation group, but this study was at high risk of bias. Meta-analysis of maximum and pain-free walking distances three months after treatment included participants with peripheral vascular disease and showed no evidence of a difference between the treatment groups (MD -31.46, 95% CI -87.63 to 24.71; 165 participants; 2 studies; low-certainty). Quality of life outcomes were reported by two studies that included participants with coronary artery disease, but we were unable to pool the data due to different methods of reporting and varied criteria. However, there did not appear to be any major differences between the treatment groups. None of the included studies reported on vascular deaths. Overall, there was no evidence of major or minor adverse events associated with EDTA chelation treatment. AUTHORS' CONCLUSIONS: There is currently insufficient evidence to determine the effectiveness or ineffectiveness of chelation therapy in improving clinical outcomes of people with atherosclerotic cardiovascular disease. More high-quality, randomised controlled trials are needed that assess the effects of chelation therapy on longevity and quality of life among people with atherosclerotic cardiovascular disease.

Exercise and Peripheral Arteriosclerosis.

Adaptation of a healthy lifestyle including adequate daily physical activity is shown to reduce 80% of cardiovascular mortality and 40% of cancer-related deaths. A large body of evidence exists proving that this relationship is dose dependent, and even half of the recommended normal physical activity yields significant risk reduction. There has been no medical therapy that would provide such high percentages of reduction in mortality to date. The World Health Organization, therefore, has started an initiative to implement exercise into daily life as a primary prevention measure. Herein, we will focus on the effects of exercise on the vasculature, mainly the peripheral vasculature, in the context of atherosclerotic disease. Exercise has a fundamental role in the pathogenesis, diagnosis, and treatment of atherosclerotic vascular disease. It exerts a protective effect against the development of atherosclerosis irrespective of other cardiovascular risk factors. Additionally, exercise induces changes in vascular hemodynamics helping us to elucidate the presence of obscure vascular involvement. Once again, exercise is the main treatment modality in peripheral arterial disease with accumulating evidence to reduce symptoms and improve both exercise capacity and cardiovascular symptoms.

Knockout of AKAP150 improves impaired BK channel-mediated vascular dysfunction through the Akt/GSK3ß signalling pathway in diabetes mellitus.

Vascular dysfunction resulting from diabetes is an important factor in arteriosclerosis. Previous studies have shown that during hyperglycaemia and diabetes, AKAP150 promotes vascular tone enhancement by intensifying the remodelling of the BK channel. However, the interaction between AKAP150 and the BK channel remains open to discussion. In this study, we investigated the regulation of impaired BK channel-mediated vascular dysfunction in diabetes mellitus. Using AKAP150 null mice (AKAP150-/- ) and wild-type (WT) control mice (C57BL/6J), diabetes was induced by intraperitoneal injection of streptozotocin. We found that knockout of AKAP150 reversed vascular remodelling and fibrosis in mice with diabetes and in AKAP150-/- diabetic mice. Impaired Akt/GSK3ß signalling contributed to decreased BK-ß1 expression in aortas from diabetic mice, and the silencing of AKAP150 increased Akt phosphorylation and BK-ß1 expression in MOVAS cells treated with HG medium. The inhibition of Akt activity caused a decrease in BK-ß1 expression, and treatment with AKAP150 siRNA suppressed GSK3ß expression in the nuclei of MOVAS cells treated with HG. Knockout of AKAP150 reverses impaired BK channel-mediated vascular dysfunction through the Akt/GSK3ß signalling pathway in diabetes mellitus.

Experimentally validated simulation of coronary stents considering different dogboning ratios and asymmetric stent positioning.

In-stent restenosis remains a major problem of arteriosclerosis treatment by stenting. Expansion-optimized stents could reduce this problem. With numerical simulations, stent designs/ expansion behaviours can be effectively analyzed. For reasons of efficiency, simplified models of balloon-expandable stents are often used, but their accuracy must be challenged due to insufficient experimental validation. In this work, a realistic stent life-cycle simulation has been performed including balloon folding, stent crimping and free expansion of the balloon-stent-system. The successful simulation and validation of two stent designs with homogenous and heterogeneous stent stiffness and an asymmetrically positioned stent on the balloon catheter confirm the universal applicability of the simulation approach. Dogboning ratio, as well as the final dimensions of the folded balloon, the crimped and expanded stent, correspond well to the experimental dimensions with only slight deviations. In contrast to the detailed stent life-cycle simulation, a displacement-controlled simulation can not predict the transient stent expansion, but is suitable to reproduce the final expanded stent shape and the associated stress states. The detailed stent life-cycle simulation is thus essential for stent expansion analysis/optimization, whereas for reasons of computational efficiency, the displacement-controlled approach can be considered in the context of pure stress analysis.

Recipient c-Kit Lineage Cells Repopulate Smooth Muscle Cells of Transplant Arteriosclerosis in Mouse Models.

RATIONALE: Transplantation-accelerated arteriosclerosis is one of the major challenges for long-term survival of patients with solid organ transplantation. Although stem/progenitor cells have been implicated to participate in this process, the cells of origin and underlying mechanisms have not been fully defined. OBJECTIVE: The objective of our study was to investigate the role of c-Kit lineage cells in allograft-induced neointima formation and to explore the mechanisms underlying this process. METHODS AND RESULTS: Using an inducible lineage tracing Kit-CreER;Rosa26-tdTomato mouse model, we observed that c-Kit is expressed in multiple cell types in the blood vessels, rather than a specific stem/progenitor cell marker. We performed allograft transplantation between different donor and recipient mice, as well as bone marrow transplantation experiments, demonstrating that recipient c-Kit+ cells repopulate neointimal smooth muscle cells (SMCs) and leukocytes, and contribute to neointima formation in an allograft transplantation model. c-Kit-derived SMCs originate from nonbone marrow tissues, whereas bone marrow-derived c-Kit+ cells mainly generate CD45+ leukocytes. However, the exact identity of c-Kit lineage cells contributing to neointimal SMCs remains unclear. ACK2 (anti-c-Kit antibody), which specifically binds and blocks c-Kit function, ameliorates allograft-induced arteriosclerosis. Stem cell factor and TGF (transforming growth factor)-ß1 levels were significantly increased in blood and neointimal lesions after allograft transplantation, by which stem cell factor facilitated c-Kit+ cell migration through the stem cell factor/c-Kit axis and downstream activation of small GTPases, MEK (mitogen-activated protein kinase kinase)/ERK (extracellular signal-regulated kinase)/MLC (myosin light chain), and JNK (c-Jun N-terminal kinase)/c-Jun signaling pathways, whereas TGF-ß1 induces c-Kit+ cell differentiation into SMCs via HK (hexokinase)-1-dependent metabolic reprogramming and a possible downstream O-GlcNAcylation of myocardin and serum response factor. CONCLUSIONS: Our findings provide evidence that recipient c-Kit lineage cells contribute to vascular remodeling in an allograft transplantation model, in which the stem cell factor/c-Kit axis is responsible for cell migration and HK-1-dependent metabolic reprogramming for SMC differentiation.

[Translating Early Vascular Aging into Clinical Practice]. / EVA (Early Vascular Aging) ­ Übersetzung in den klinischen Alltag.

Early Vascular Aging, a concept describing pathophysiologic and clinical aspects of premature arterial stiffness and arteriosclerosis, has attracted attention in recent years. Early diagnosis and intervention is essential for prevention and postponing cardiovascular events.

Complexity in disease management: A linked data analysis of multimorbidity in Aboriginal and non-Aboriginal patients hospitalised with atherothrombotic disease in Western Australia.

BACKGROUND: Hospitalisation for atherothrombotic disease (ATD) is expected to rise in coming decades. However, increasingly, associated comorbidities impose challenges in managing patients and deciding appropriate secondary prevention. We investigated the prevalence and pattern of multimorbidity (presence of two or more chronic conditions) in Aboriginal and non-Aboriginal Western Australian residents with ATDs. METHODS AND FINDINGS: We used population-based de-identified linked administrative health data from 1 January 2000 to 30 June 2014 to identify a cohort of patients aged 25-59 years admitted to Western Australian hospitals with a discharge diagnosis of ATD. The prevalence of common chronic diseases in these patients was estimated and the patterns of comorbidities and multimorbidities empirically explored using two different approaches: identification of the most commonly occurring pairs and triplets of comorbid diseases, and through latent class analysis (LCA). Half of the cohort had multimorbidity, although this was much higher in Aboriginal people (Aboriginal: 79.2% vs. non-Aboriginal: 39.3%). Only a quarter were without any documented comorbidities. Hypertension, diabetes, alcohol abuse disorders and acid peptic diseases were the leading comorbidities in the major comorbid combinations across both Aboriginal and non-Aboriginal cohorts. The LCA identified four and six distinct clinically meaningful classes of multimorbidity for Aboriginal and non-Aboriginal patients, respectively. Out of the six groups in non-Aboriginal patients, four were similar to the groups identified in Aboriginal patients. The largest proportion of patients (33% in Aboriginal and 66% in non-Aboriginal) was assigned to the "minimally diseased" (or relatively healthy) group, with most patients having less than two conditions. Other groups showed variability in degree and pattern of multimorbidity. CONCLUSION: Multimorbidity is common in ATD patients and the comorbidities tend to interact and cluster together. Physicians need to consider these in their clinical practice. Different treatment and secondary prevention strategies are likely to be useful for management in these cluster groups.

[Effects of 16 week aerobic exercise on baPWV and ABI of middle-aged and elderly patients].

OBJECTIVES: To investigate the interventional effects of 16-week aerobic exercises on the elderly's arteriosclerosis and its mechanism. METHODS: Twenty-seven elderly people with the average age of 62. 70 ±3. 26 joined a 16-week square dance/taijiquan exercise program that conducted 60 minutes each time, six times per week. Arterial stiffness and its related indexes such as systolic pressure(SBP), diastolic pressure(DBP), left brachial-ankle pulse wave velocity (L-baPWV), right brachial-ankle pulse wave velocity(R-baPWV), left ankle brachial index (L-ABI), right ankle brachial index(R-ABI), serum triglyceride(TG), total cholesterol(TC), high density lipoprotein cholesterol(HDL-c), low density lipoprotein cholesterol(LDL-c), superoxide dismutase(SOD), malondialdehyde(MDA) and glutathione peroxidase (GSH-Px) were detected at 3 time points including before exercise program, by the end of exercise for 8 weeks and 16 weeks. RESULTS: ① Compared with pre-exercise, the R-baPWV and R-ABI of the elderly people were decreased at the end of the 8th week, and the L-baPWV, RbaPWV, R-ABI and L-ABI were decreased significantly at the end of the 16th week. ②Compared with pre-exercise, SBP and DBP were declined markedly (P<0.01, P<0.05) at the end of the 8th week, SBP, DBP and pulse pressure were decreased significantly (P<0.01, P<0.05) at the end of the 16th week. ③Compared with pre-exercise, TC and LDL-c were declined markedly (P<0.01) at the end of the 8th and the 16th week, and there was no difference of the level of TG and LDL-c between pre-exercise and post-exercise. ④There was no evident difference of serum level of SOD, GSH-Px, MDA between pre-exercise and post-exercise at the end of the 8th week. Compared with pre-exercise, the level of serum SOD, GSH-Px was increased evidently while the content of serum MDA was decreased significantly (P<0.01). CONCLUSIONS: Sixteen-week aerobic exercises could reduce baPWV and ABI levels, regulate blood pressure, blood lipids and lipid peroxides levels of the elderly evidently, thus improve the controlling quality of atherosclerosis.

Interaction between Albuminuria and Treatment Group Outcomes for Patients with Renal Artery Stenosis: The NITER Study.

PURPOSE: To perform a post-hoc analysis of the Nephropathy Ischemic Therapy (NITER) trial, which enrolled patients with atherosclerotic renal artery stenosis, to evaluate whether medical therapy plus stent placement is superior to medical therapy alone in patients without elevated albuminuria. MATERIALS AND METHODS: Data from 51 patients were analyzed and stratified into 2 cohorts by median urinary albumin (UAlb) levels: cohort 1 ("low albuminuria," UAlb ≤0.04 g/24h) and cohort 2 ("high albuminuria," UAlb >0.04g/24h). Interaction effect between treatment arms and UAlb cohorts was calculated using Cox regression analysis. Survival analysis was followed by test for effect size, power analysis, and construction of a Kaplan-Meier survival table. RESULTS: At study completion, 13 patients had an outcome event: 6 (23%) from cohort 1 and 7 (28%) from cohort 2. Patients in cohort 1 had event-free survival of 83% at 3.9 ± 0.3 years from the primary endpoints of all-cause mortality, dialysis, and cardiovascular events when treated with interventional therapy, compared to 45% when treated with medical therapy alone (P = .501), which showed a 62% treatment effect for stent placement. In cohort 2, event-free survival rates were 64% for medical therapy versus 52% for medical plus interventional therapy (P = .64). Using Cox regression analysis, the interaction effect between treatment arms and UAlb cohorts was not significant (P = .32). The power of the study to detect an interaction effect, if one existed, was only 15%. CONCLUSIONS: Inference cannot be drawn for similar populations because of inadequate sample size, but, in this sample, patients treated with stent placement who had low albuminuria had better outcomes than patients treated with medical therapy alone.

The differentiation of mesenchymal stem cells to vascular cells regulated by the HMGB1/RAGE axis: its application in cell therapy for transplant arteriosclerosis.

BACKGROUND: Mesenchymal stem cell (MSC) transplantation shows promise for treating transplant arteriosclerosis, at least partly via promoting endothelial regeneration. However, the efficacy and safety are still under investigation especially regarding recent findings that neointimal smooth muscle cells are derived from MSC-like cells. The high mobility group box 1 (HMGB1)/receptor for advanced glycation end-product (RAGE) axis is involved in regulating proliferation, migration, and differentiation of MSCs, and therefore it can be presumably applied to improve the outcome of cell therapy. The aim of the current study was to investigate this hypothesis. METHODS: Rat MSCs were treated with HMGB1 or modified with HMGB1 vectors to activate the HMGB1/RAGE axis. RAGE was targeted and inhibited by specific short hairpin RNA vectors. We assessed the capacity for cell proliferation, migration, and differentiation after vector transfection in vitro and in a rat model of transplant arteriosclerosis. The expression of CD31 and α-smooth muscle actin (αSMA) was determined to evaluate the differentiation of MSCs to endothelial cells and smooth muscle cells. RESULTS: Exogenous HMGB1 treatment and transfection with HMGB1 vectors promoted MSC migration and vascular endothelial growth factor (VEGF)-induced differentiation to CD31+ cells while inhibiting their proliferation and platelet-derived growth factor (PDGF)-induced differentiation to αSMA+ cells. Such an effect was blocked by RAGE knockdown. HMGB1-modified cells preferably migrated to graft neointima and differentiated to CD31+ cells along with significant relief of transplant arteriosclerosis and inhibition of HMGB1 and RAGE expression in graft vessels. RAGE knockdown inhibited cell migration to graft vessels. CONCLUSIONS: HMGB1 stimulated MSCs to migrate and differentiate to endothelial cells via RAGE signaling, which we translated to successful application in cell therapy for transplant arteriosclerosis.

Decalogue of the Spanish Society of Arteriosclerosis to reduce therapeutic inertia. / Decálogo de la Sociedad Española de Arteriosclerosis para disminuir la inercia terapéutica.

Therapeutic inertia (TI) is defined as the failure of the physician to initiate or intensify a treatment when the therapeutic goal has not been achieved. TI can be of 2types: inertia due to lack of prescription of drugs and inertia in the absence of control of a risk factor. The consequences of TI are poor control of risk factors, an increase in potentially preventable events and an increase in costs. There are factors of the doctor himself, the patient and the care organization that determine the presence of TI. Ten measures are proposed to reduce TI: to promote continuing education, to define clearly therapeutic objectives, to establish audits, to implement computerized medical records with alerts, to encourage research in this field, to disseminate clinical practice guidelines, to create motivational incentives, to organize care, to improve the doctor-patient relationship and to involve other health care providers.

Central Hemodynamics for Management of Arteriosclerotic Diseases.

Arteriosclerosis, particularly aortosclerosis, is the most critical risk factor associated with cardiovascular, cerebrovascular, and renal diseases. The pulsatile hemodynamics in the central aorta consists of blood pressure, flow, and stiffness and substantially differs from the peripheral hemodynamics in muscular arteries. Arteriosclerotic changes with age appear earlier in the elastic aorta, and age-dependent increases in central pulse pressure are more marked than those apparent from brachial pressure measurement. Central pressure can be affected by lifestyle habits, metabolic disorders, and endocrine and inflammatory diseases in a manner different from brachial pressure. Central pulse pressure widening due to aortic stiffening increases left ventricular afterload in systole and reduces coronary artery flow in diastole, predisposing aortosclerotic patients to myocardial hypertrophy and ischemia. The widened pulse pressure is also transmitted deep into low-impedance organs such as the brain and kidney, causing microvascular damage responsible for lacunar stroke and albuminuria. In addition, aortic stiffening increases aortic blood flow reversal, which can lead to retrograde embolic stroke and renal function deterioration. Central pressure has been shown to predict cardiovascular events in most previous studies and potentially serves as a surrogate marker for intervention. Quantitative and comprehensive evaluation of central hemodynamics is now available through various noninvasive pressure/flow measurement modalities. This review will focus on the clinical usefulness and mechanistic rationale of central hemodynamic measurements for cardiovascular risk management.