Landiolol for Treatment of New-Onset Atrial Fibrillation in Critical Care: A Systematic Review.

Background: new-onset atrial fibrillation remains a common complication in critical care settings, often necessitating treatment when the correction of triggers is insufficient to restore hemodynamics. The treatment strategy includes electric cardioversion in cases of hemodynamic instability and either rhythm control or rate control in the absence of instability. Landiolol, an ultrashort beta-blocker, effectively controls heart rate with the potential to regulate rhythm. Objectives This review aims to compare the efficacy of landiolol in controlling heart rate and converting to sinus rhythm in the critical care setting. Methods: We conducted a comprehensive review of the published literature from 2000 to 2022 describing the use of landiolol to treat atrial fibrillation in critical care settings, excluding both cardiac surgery and medical cardiac care settings. The primary outcome assessed was sinus conversion following landiolol treatment. Results: Our analysis identified 17 publications detailing the use of landiolol for the treatment of 324 critical care patients. While the quality of the data was generally low, primarily comprising non-comparative studies, landiolol consistently demonstrated similar efficacy in controlling heart rate and facilitating conversion to sinus rhythm in both non-surgical (75.7%) and surgical (70.1%) settings. The incidence of hypotension associated with landiolol use was 13%. Conclusions: The use of landiolol in critical care patients with new-onset atrial fibrillation exhibited comparable efficacy and tolerance in both non-surgical and surgical settings. Despite these promising results, further validation through randomized controlled trials is necessary.

Lung epithelial and myeloid innate immunity in influenza-associated or COVID-19-associated pulmonary aspergillosis: an observational study.

BACKGROUND: Influenza-associated pulmonary aspergillosis (IAPA) and COVID-19-associated pulmonary aspergillosis (CAPA) affect about 15% of critically ill patients with influenza or COVID-19, respectively. These viral-fungal coinfections are difficult to diagnose and are associated with increased mortality, but data on their pathophysiology are scarce. We aimed to explore the role of lung epithelial and myeloid innate immunity in patients with IAPA or CAPA. METHODS: In this observational study, we retrospectively recruited patients who had been admitted to the intensive care unit (ICU) of University Hospitals Leuven, Belgium, requiring non-invasive or invasive ventilation because of severe influenza or COVID-19, with or without aspergillosis, between Jan 1, 2011, and March 31, 2021, whose bronchoalveolar lavage samples were available at the hospital biobank. Additionally, biobanked in vivo tracheobronchial biopsy samples from patients with IAPA or CAPA and invasive Aspergillus tracheobronchitis admitted to ICUs requiring invasive ventilation between the same dates were collected from University Hospitals Leuven, Hospital Network Antwerp (Belgium), and Amiens-Picardie University Hospital (France). We did nCounter gene expression analysis of 755 genes linked to myeloid innate immunity and protein analysis of 47 cytokines, chemokines, and growth factors on the bronchoalveolar lavage samples. Gene expression data were used to infer cell fractions by use of CIBERSORTx, to perform hypergeometric enrichment pathway analysis and gene set enrichment analysis, and to calculate pathway module scores for the IL-1ß, TNF-α, type I IFN, and type II IFN (IFNγ) pathways. We did RNAScope targeting influenza virus or SARS-CoV-2 RNA and GeoMx spatial transcriptomics on the tracheobronchial biopsy samples. FINDINGS: Biobanked bronchoalveolar lavage samples were retrieved from 166 eligible patients, of whom 40 had IAPA, 52 had influenza without aspergillosis, 33 had CAPA, and 41 had COVID-19 without aspergillosis. We did nCounter gene expression analysis on bronchoalveolar lavage samples from 134 patients, protein analysis on samples from 162 patients, and both types of analysis on samples from 130 patients. We performed RNAScope and spatial transcriptomics on the tracheobronchial biopsy samples from two patients with IAPA plus invasive Aspergillus tracheobronchitis and two patients with CAPA plus invasive Aspergillus tracheobronchitis. We observed a downregulation of genes associated with antifungal effector functions in patients with IAPA and, to a lesser extent, in patients with CAPA. We found a downregulated expression of several genes encoding proteins with functions in the opsonisation, recognition, and killing of conidia in patients with IAPA versus influenza only and in patients with CAPA versus COVID-19 only. Several genes related to LC3-associated phagocytosis, autophagy, or both were differentially expressed. Patients with CAPA had significantly lower neutrophil cell fractions than did patients with COVID-19 only. Patients with IAPA or CAPA had downregulated IFNγ signalling compared with patients with influenza only or COVID-19 only, respectively. The concentrations of several fibrosis-related growth factors were significantly elevated in the bronchoalveolar lavage fluid from patients with IAPA versus influenza only and from patients with CAPA versus COVID-19 only. In one patient with CAPA, we visualised an active or very recent SARS-CoV-2 infection disrupting the epithelial barrier, facilitating tissue-invasive aspergillosis. INTERPRETATION: Our results reveal a three-level breach in antifungal immunity in IAPA and CAPA, affecting the integrity of the epithelial barrier, the capacity to phagocytise and kill Aspergillus spores, and the ability to destroy Aspergillus hyphae, which is mainly mediated by neutrophils. The potential of adjuvant IFNγ in the treatment of IAPA and CAPA should be investigated. FUNDING: Research Foundation Flanders, Coronafonds, the Max Planck Society, the Fundação para a Ciência e a Tecnologia, the European Regional Development Fund, "la Caixa" Foundation, and Horizon 2020.

Pathology Assessments of Multiple Organs in Fatal COVID-19 in Intensive Care Unit vs. Non-intensive Care Unit Patients.

Purpose: The objective of the present study was to provide a detailed histopathological description of fatal coronavirus disease 2019 (COVID 19), and compare the lesions in Intensive Care Unit (ICU) and non-ICU patients. Methods: In this prospective study we included adult patients who died in hospital after presenting with confirmed COVID-19. Multiorgan biopsies were performed. Data generated with light microscopy, transmission electron microscopy (TEM) and RT-PCR assays were reviewed. Results: 20 patients were enrolled in the study and the main pulmonary finding was alveolar damage, which was focal in 11 patients and diffuse in 8 patients. Chronic fibrotic and inflammatory lesions were observed in 18 cases, with acute inflammatory lesions in 12 cases. Diffuse lesions, collapsed alveoli and dystrophic pneumocytes were more frequent in the ICU group (62.5%, vs. 25%; 63%, vs. 55%; 87.5%, vs. 54%). Acute lesions (82%, vs. 37.5%; p = 0.07) with neutrophilic alveolitis (63.6% vs. 0%, respectively; p = 0.01) were observed more frequently in the non-ICU group. Viral RNA was detected in 12 lung biopsies (60%) up to 56 days after disease upset. TEM detected viral particles in the lung and kidney biopsy samples up to 27 days after disease upset. Furthermore, abundant networks of double-membrane vesicles (DMVs, a hallmark of viral replication) were observed in proximal tubular epithelial cells. Conclusion: Lung injury was different in ICU and non-ICU patients. Extrapulmonary damage consisting in kidney and myocardial injury were more frequent in ICU patients. Our TEM experiments provided the first description of SARS-CoV-2-induced DMVs in kidney biopsy samples-a sign of intense viral replication in this organ.

Temozolomide is a risk factor for invasive pulmonary aspergillosis: A case report and literature review.

BACKGROUND: Temozolomide is an oral alkylating agent incorporated in the treatment of glioblastoma multiforme (GBM) that can lead to lymphopenia. The standard treatment of GBM involves temozolomide chemotherapy with radiation, often with addition of corticosteroids for symptomatic management of cerebral edema. Some studies have reported an increased risk of opportunistic infections. CASE PRESENTATION: A 72-year-old man receiving Temozolomide for treatment of newly diagnosed GBM associated with radiotherapy and corticosteroids was admitted in an intensive care unit because a rapid deterioration of consciousness associated with acute respiratory failure. The diagnosis of invasive pulmonary aspergillosis (IPA) was made. The patient was successfully treated with voriconazole alone. CONCLUSIONS: This case shows that Temozolomide can be associated with severe invasive aspergillosis, which is in all likelihood associated with T lymphocyte immune dysfunction. Physicians should be aware of possible opportunistic infections when managing patients with glioblastoma, and patients exposed to this agent should be carefully monitored.

From Upper Respiratory Symptoms to Hemophagocytic Lymphohistiocytosis: Case Report of a Human Adenovirus Infection in Haploidentical Hematopoietic Stem Cell Transplant Recipient.

Human adenovirus infection is rare in adult population, except for in immunocompromised individuals. Recipients of allogenic haploidentical hematopoietic stem cell transplantation are reported at high risk for human adenovirus, which is often lethal when it evolves into the disseminated form. Despite existent guidelines, prevention, early diagnosis, and therapeutics remain challenging. Here, we report the case of a fatal evolution of human adenovirus respiratory infection and discuss the actual recommendations to prevent recurrence of this major issue.

Two rapid, accurate liquid chromatography tandem mass spectrometry methods for the quantification of seven uremic toxins: An application for describing their accumulation kinetic profile in a context of acute kidney injury.

Acute kidney injury (AKI) is a frequent, serious complication in critically ill patients. Even if renal replacement therapy is rapidly initiated, AKI may lead to the acute accumulation of metabolic waste products called uremic toxins (UTs). Although the accumulation and effects of UTs have been extensively described in the setting of chronic kidney disease (CKD), few data are available for AKI. A rapid, sensitive, specific method with simple sample preparation is required to facilitate routine blood monitoring of UTs in a context of acute accumulation. We have developed and validated two fast liquid chromatography tandem mass spectrometry methods for the quantification of seven UTs in human serum. The first method (in negative ionization mode) enables the quantification of five UTs (hippuric acid (HA), indoxyl sulfate (IxS), para-cresyl sulfate (pCS), para-cresyl glucuronide (pCG), 3-carboxy-4-methyl-5-propyl-2-furanpropionate (CMPF)). The second method (in positive ionization mode) enables the quantification of two UTs (indole-3-acetic acid (IAA), and trimethylamine N-oxide (TMAO)). Sample preparation consisted of the deproteinization of a small volume of serum (50 µL). The run-times required to assay all the UTs in negative and positive ionization modes were only 2.5 and 2 min, respectively. In order to obtain a reliable, toxin-free matrix for the preparation of calibration standards and quality controls, serum was pretreated with activated charcoal. We used these methods to determine the time course of UT accumulation in eight patients who developed an AKI after cardiac surgery. The calibration curves ranged from 0.1 to 100 µg mL-1 for all the UTs (except for IAA: 0.5 to 100 µg mL-1), and the correlation coefficients were above 0.999 for all. The methods were reproducible, repeatable, and accurate, with all coefficients of variation and biases below 15%. The highest concentrations measured in patients with AKI were lower than those reported in CKD stages 4 and 5 but higher than those observed in patients with no impairment of renal function (particularly for IxS and pCS). Our results also highlighted low accumulation of the other toxins (IAA, HA, TMAO, pCG, and CMPF). The UT concentrations did not rise earlier than that of creatinine; although the return to baseline took longer than for creatinine for some compounds. Lastly, assessment of the time course of UT accumulation as a prognostic marker for AKI (particularly for pCS and IxS) appears to be promising and should be continued in a larger number of patients.

Invasive Tracheobronchial Aspergillosis in Critically Ill Patients with Severe Influenza. A Clinical Trial.

Rationale: Invasive tracheobronchial aspergillosis (ITBA) is an uncommon but severe clinical form of invasive pulmonary aspergillosis in which the fungal infection is entirely or predominantly confined to the tracheobronchial tree.Objectives: To analyze the diagnostic and prognostic differences between tracheobronchial aspergillosis and pulmonary aspergillosis without tracheobronchial lesions among patients admitted to the ICU with severe influenza.Methods: This retrospective, observational study included critically ill patients with influenza associated with pulmonary aspergillosis from three hospital ICUs between 2010 and 2019. Patient characteristics and clinical and mycologic data at admission and during ICU stay were collected in a database to evaluate variables in the two groups.Measurements and Main Results: Thirty-five patients admitted to the ICU with severe influenza and pulmonary aspergillosis were included. Ten patients were included in the group with ITBA (n = 10 of 35; 28.6%), and 25 patients were included in the group without ITBA. The group with ITBA comprised more patients with active smoking, diabetes mellitus, and higher severity scores (Simplified Acute Physiology Score II). Ninety-day mortality rates in the groups with and without ITBA were 90% and 44%, respectively (P = 0.02). Moreover, significantly higher serum 1,3-ß-d-glucan and galactomannan and BAL fluid galactomannan concentrations were observed in the group with ITBA compared with the group without ITBA (P < 0.0001, P = 0.003, and P = 0.008, respectively).Conclusions: ITBA was associated with higher severity scores, mortality, and serum and BAL fluid galactomannan and 1,3-ß-d-glucan concentrations than invasive pulmonary aspergillosis without tracheobronchial lesions. ITBA should be systematically researched by bronchoscopic examination in ICU patients with concomitant pulmonary aspergillosis and influenza.Clinical trial registered with www.clinicaltrials.gov (NCT04077697).

The Warburg Effect as a Type B Lactic Acidosis in a Patient With Acute Myeloid Leukemia: A Diagnostic Challenge for Clinicians.

INTRODUCTION: The Warburg effect (WE) is an uncommon cause of type B lactic acidosis (LA) due to a deregulation of carbohydrate metabolism in neoplastic cells where lactic fermentation predominates over oxidative phosphorylation regardless of the oxygen level. CASE PRESENTATION: We report the case of a 57-year-old man presenting with concomitant acute myeloid leukemia and type B LA with asymptomatic hypoglycemia. We did not find arguments for a septic state, liver dysfunction, or acute mesenteric ischemia. The WE was suspected, and chemotherapy was immediately undertaken. We observed a rapid and sustained decrease in lactate level and normalization of blood glucose. Unfortunately, we noted a relapse of acute leukemia associated with WE soon after treatment initiation and the patient died in the Intensive Care unit. DISCUSSION: Some patients may present complications directly related to an underlying hematological malignancy. The WE is one of these complications and should be suspected in patients with both hypoglycemia and LA. We propose a checklist in order to help clinicians manage this life-threatening complication. Before considering WE, clinicians should eliminate diagnoses such as septic shock or mesenteric ischemia, which require urgent and specific management. CONCLUSION: The diagnosis of WE can be challenging for clinicians in the Hematology department and the Intensive Care unit. Prompt diagnosis and rapid, adapted chemotherapy initiation may benefit patient survival.

The presence of elastic compression stockings reduces the fluid responsiveness of patients in the operating room.

BACKGROUND: The aim of this study was to investigate whether elastic compression stockings (ECS) can affect fluid responsiveness parameters before and during passive leg raising (PLR) maneuvers. METHODS: In the operating room (OR), we performed a prospective study including patients referred for cardiac surgery. Blood pressure (BP), ΔPP, heart rate (HR), central venous pressure (CVP), stroke volume (SV) and aortic blood flow (ABF) (by esophageal doppler) were measured according to four conditions: supine position without ECS (baseline 1), lower limbs raised to an angle of 45° (PLR 1), returned to the supine position with ECS (baseline 2), then a second PLR maneuver with ECS was performed (PLR 2). RESULTS: Twenty patients were included. BP, SV, ABF and CVP increased significantly. ΔPP and HR decreased during PLR 1. At baseline 2, HR and ΔPP decreased significantly compared to baseline 1. During PLR 2, increase of SV (4% [9]) and ABF (4% [9]), and the decrease of ΔPP (-19% [104]) were significantly lower than those observed at PLR 1 (7% [21] P=0.05; 9% [8] P=0.02 and -66% [40] P=0.02, respectively). Eleven patients presented a ΔPP≥13% at baseline 1. Only 1 patient still presented a ΔPP≥13% with ECS at baseline 2. Only 3/9 patients with an increase of ABF ≥10% and 2/11 patients with an increase of PP ≥12% during the PLR 1 presented similar results during PLR 2. CONCLUSIONS: In the OR, ECS provoke a self-fluid loading increasing ABF, decreasing ΔPP and PLR response. The presence of ECS should be considered when managing hemodynamic parameters of patients.

Urgent Chemotherapy for Life-Threatening Complications Related to Solid Neoplasms.

OBJECTIVES: Solid neoplasms can be directly responsible for organ failures at the time of diagnosis or relapse. The management of such specific complications relies on urgent chemotherapy and eventual instrumental or surgical procedures, combined with advanced life support. We conducted a multicenter study to address the prognosis of this condition. DESIGN: A multicenter retrospective (2001-2015) chart review. SETTING: Medical and respiratory ICUs. PATIENTS: Adult patients who received urgent chemotherapy in the ICU for organ failure related to solid neoplasms were included. The modalities of chemotherapy, requirements of adjuvant instrumental or surgical procedures, and organ supports were collected. Endpoints were short- and long-term survival rates. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: One hundred thirty-six patients were included. Lung cancer was the most common malignancy distributed into small cell lung cancer (n = 57) and non-small cell lung cancer (n = 33). The main reason for ICU admission was acute respiratory failure in 111 patients (81.6%), of whom 89 required invasive mechanical ventilation. Compression and tissue infiltration by tumor cells were the leading mechanisms resulting in organ involvement in 78 (57.4%) and 47 (34.6%) patients. The overall in-ICU, in-hospital, 6-month, and 1-year mortality rates were 37%, 58%, 74%, and 88%, respectively. Small cell lung cancer was identified as an independent predictor of hospital survival. However, this gain in survival was not sustained since the 1-year survival rates of small cell lung cancer, non-small cell lung cancer, and non-lung cancer patients all dropped below 20%. CONCLUSIONS: Urgent chemotherapy along with aggressive management of organ failures in the ICU can be lifesaving in very selected cancer patients, most especially with small cell lung cancer, although the long-term survival is hardly sustainable.

Thrombotic Microangiopathy Revealing Bone Metastases from an Ethmoid Sinus Carcinoma.

Cancer-related thrombotic microangiopathy (TMA) is a rare entity whose clinical and biological characteristics have been described in various tumors. Here we describe the first case of cancer-related TMA revealing diffuse bone metastases from an ethmoid sinus carcinoma.

Low-gradient, low-flow severe aortic stenosis with preserved left ventricular ejection fraction: characteristics, outcome, and implications for surgery.

BACKGROUND: Severe low-gradient, low-flow (LG/LF) aortic stenosis with preserved left ventricular ejection fraction (EF) has been described as a more advanced form of aortic stenosis. However, the natural history and need for surgery in patients with LG/LF aortic stenosis remain subjects of intense debate. OBJECTIVES: We sought to investigate the outcome of LG/LF aortic stenosis in comparison with moderate aortic stenosis and with high-gradient (HG) aortic stenosis in a real-world study, in the context of routine practice. METHODS: This analysis included 809 patients (ages 75 ± 12 years) diagnosed with aortic stenosis and preserved EF (≥50%). Patients were divided into 4 groups: mild-to-moderate aortic stenosis; HG aortic stenosis; LG/LF aortic stenosis; and low-gradient, normal-flow (LG/NF) aortic stenosis. RESULTS: Compared with mild-to-moderate aortic stenosis patients, LG/LF aortic stenosis patients had smaller valve areas and stroke volumes, higher mean gradients, and comparable degrees of ventricular hypertrophy. Under medical management (22.8 months; range 7 to 53 months), compared with mild-to-moderate aortic stenosis patients, HG aortic stenosis patients were at higher risk of death (adjusted hazard ratio [HR]: 1.47; 95% confidence interval [CI]: 1.03 to 2.07), whereas LG/LF aortic stenosis patients did not have an excess mortality risk (adjusted HR: 0.88; 95% CI: 0.53 to 1.48). During the entire (39.0 months; range 11 to 69 months) follow-up (with medical and surgical management), the mortality risk associated with LG/LF aortic stenosis was close to that of mild-to-moderate aortic stenosis (adjusted HR: 0.96; 95% CI: 0.58 to 1.53), whereas the excess risk of death associated with HG aortic stenosis was confirmed (adjusted HR: 1.74; 95% CI: 1.27 to 2.39). The benefit associated with aortic valve replacement was confined to the HG aortic stenosis group (adjusted HR: 0.29; 95% CI: 0.18 to 0.46) and was not observed for LG/LF aortic stenosis (adjusted HR: 0.75; 95% CI: 0.14 to 4.05). CONCLUSIONS: In this study, the outcome of severe LG/LF aortic stenosis with preserved EF was similar to that of mild-to-moderate aortic stenosis and was not favorably influenced by aortic surgery. Further research is needed to better understand the natural history and the progression of LG/LF aortic stenosis.

Curtailing endothelial TGF-ß signaling is sufficient to reduce endothelial-mesenchymal transition and fibrosis in CKD.

Excessive TGF-ß signaling in epithelial cells, pericytes, or fibroblasts has been implicated in CKD. This list has recently been joined by endothelial cells (ECs) undergoing mesenchymal transition. Although several studies focused on the effects of ablating epithelial or fibroblast TGF-ß signaling on development of fibrosis, there is a lack of information on ablating TGF-ß signaling in the endothelium because this ablation causes embryonic lethality. We generated endothelium-specific heterozygous TGF-ß receptor knockout (TßRII(endo+/-)) mice to explore whether curtailed TGF-ß signaling significantly modifies nephrosclerosis. These mice developed normally, but showed enhanced angiogenic potential compared with TßRII(endo+/+) mice under basal conditions. After induction of folic acid nephropathy or unilateral ureteral obstruction, TßRII(endo+/-) mice exhibited less tubulointerstitial fibrosis, enhanced preservation of renal microvasculature, improvement in renal blood flow, and less tissue hypoxia than TßRII(endo+/+) counterparts. In addition, partial deletion of TßRII in the endothelium reduced endothelial-to-mesenchymal transition (EndoMT). TGF-ß-induced canonical Smad2 signaling was reduced in TßRII(+/-) ECs; however, activin receptor-like kinase 1 (ALK1)-mediated Smad1/5 phosphorylation in TßRII(+/-) ECs remained unaffected. Furthermore, the S-endoglin/L-endoglin mRNA expression ratio was significantly lower in TßRII(+/-) ECs compared with TßRII(+/+) ECs. These observations support the hypothesis that EndoMT contributes to renal fibrosis and curtailing endothelial TGF-ß signals favors Smad1/5 proangiogenic programs and dictates increased angiogenic responses. Our data implicate endothelial TGF-ß signaling and EndoMT in regulating angiogenic and fibrotic responses to injury.

Sirtuin 1 ablation in endothelial cells is associated with impaired angiogenesis and diastolic dysfunction.

Discordant myocardial growth and angiogenesis can explain left ventricular (LV) hypertrophy progressing toward heart failure with aging. Sirtuin 1 expression declines with age; therefore we explored the role played by angiogenesis and Sirtuin 1 in the development of cardiomyopathy. We compared the cardiac function of 10- to 15-wk-old (wo), 30-40 wo, and 61-70 wo endothelial Sirtuin 1-deleted (Sirt1(endo-/-)) mice and their corresponding knockout controls (Sirt1(Flox/Flox)). After 30-40 wk, Sirt1(endo-/-) animals exhibited diastolic dysfunction (DD), decreased mRNA expression of Serca2a in the LV, and decreased capillary density compared with control animals despite a similar VEGFa mRNA expression. However, LV fibrosis and hypoxia-inducible factor (HIF)1α expression were not different. The creation of a transverse aortic constriction (TAC) provoked more severe DD and LV fibrosis in Sirt1(endo-/-) compared with control TAC animals. Although the VEGFa mRNA expression was not different and the protein expression of HIF1α was higher in the Sirt1(endo-/-) TAC animals, capillary density remained reduced. In cultured endothelial cells administration of Sirtuin 1 inhibitor decreased mRNA expression of VEGF receptors FLT 1 and FLK 1. Ex vivo capillary sprouting from aortic explants showed impaired angiogenic response to VEGF in the Sirt1(endo-/-) mice. In conclusion, the data demonstrate 1) a defect in angiogenesis preceding development of DD; 2) dispensability of endothelial Sirtuin 1 under unstressed conditions and during normal aging; and 3) impaired angiogenic adaptation and aggravated DD in Sirt1(endo-/-) mice challenged with LV overload.

Endostatin and kidney fibrosis in aging: a case for antagonistic pleiotropy?

A recurring theme of a host of gerontologic studies conducted in either experimental animals or in humans is related to documenting the functional decline with age. We hypothesize that elevated circulating levels of a powerful antiangiogenic peptide, endostatin, represent one of the potent systemic causes for multiorgan microvascular rarefaction and functional decline due to fibrosis. It is possible that during the life span of an organism there is an accumulation of dormant transformed cells producing antiangiogenic substances (endostatin) that maintain the dormancy of such scattered malignant cells. The proof of this postulate cannot be obtained by physically documenting these scattered cells, and it rests exclusively on the detection of sequelae of shifted pro- and antiangiogenic balance toward the latter. Here we compared circulating levels of endostatin in young and aging mice of two different strains and showed that endostatin levels are elevated in the latter. Renal expression of endostatin increased ~5.6-fold in aging animals. This was associated with microvascular rarefaction and progressive tubulointerstitial fibrosis. In parallel, the levels of sirtuins 1 and 3 were significantly suppressed in aging mice in conjunction with the expression of markers of senescence. Treating young mice with endostatin for 28 days showed delayed recovery of circulation after femoral artery ligation and reduced patency of renal microvasculature but no fibrosis. In conclusion, the findings are consistent with the hypothesis on elevation of endostatin levels and parallel microvascular rarefaction and induction of renal fibrosis in aging mice.

Farnesyltransferase inhibitor R115777 protects against vascular disease in uremic mice.

BACKGROUND: Atherosclerosis and vascular calcification are major contributors to cardiovascular morbidity and mortality among chronic kidney disease patients. The mevalonate pathway may play a role in this vascular pathology. Farnesyltransferase inhibitors such as R115777 block one branch of mevalonate pathway. We studied the effects of farnesyltransferase inhibitor R115777 on vascular disease in apolipoprotein E deficient mice with chronic renal failure and on mineral deposition in vitro. METHODS AND RESULTS: Female uremic and non-uremic apolipoprotein E deficient mice were randomly assigned to four groups and treated with either farnesyltransferase inhibitor R115777 or vehicle. Farnesyltransferase inhibitor R115777 inhibited protein prenylation in mice with chronic renal failure. It decreased aortic atheromatous lesion area and calcification in these animals, and reduced vascular nitrotyrosine expression and total collagen as well as collagen type I content. Proteomic analysis revealed that farnesyltransferase inhibitor corrected the chronic renal failure-associated increase in serum apolipoprotein IV and α globin, and the chronic renal failure-associated decrease in serum fetuin A. Farnesyltransferase inhibitor further inhibited type I collagen synthesis and reduced mineral deposition in vascular smooth muscle cells in vitro, probably involving Ras-Raf pathway. CONCLUSIONS: We show for the first time that farnesyltransferase inhibition slows vascular disease progression in chronic renal failure by both indirect systemic and direct local actions. This beneficial effect was mediated via a reduction in oxidative stress and favorable changes in vasoprotective peptides.

Mechanisms of aortic and cardiac dysfunction in uremic mice with aortic calcification.

BACKGROUND: Chronic renal failure (CRF) is associated with cardiac dysfunction and increased aortic stiffness. The mechanisms involved are not clearly understood. We examined changes over time in cardiac and aortic function in a murine CRF model. METHODS AND RESULTS: Eight-week-old mice were randomly assigned to 1 of 4 groups: wild-type non-CRF, wild-type CRF, apolipoprotein E knockout non-CRF, and apolipoprotein E knockout CRF. Echocardiography was performed and blood samples were taken at baseline and after 6 and 10 weeks of CRF. Vascular reactivity and adhesion molecule expression were studied after 6 and 10 weeks of CRF. Left ventricular hypertrophy, altered left ventricular relaxation, and increased aortic stiffness were observed after 6 weeks of CRF and persisted after 10 weeks. The 4 groups of mice did not significantly differ in terms of arterial blood pressure and aortic structure. The degree of vascular calcification and serum total cholesterol concentration were higher in the CRF groups than in the non-CRF groups. These changes, however, could not explain the cardiac and vascular differences seen in the 2 CRF groups. In contrast, alterations in vascular reactivity, the upregulation of adhesion molecule expression, and CRF status were significantly associated with these changes. CONCLUSIONS: In a mouse model of CRF, left ventricular hypertrophy, cardiac diastolic dysfunction, and increased aortic stiffness were not related to structural changes in the aorta (including aortic calcification) or high serum cholesterol levels. However, cardiac and aortic abnormalities were associated with the extent of subendothelial dysfunction and the severity of CRF.