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1.
J Bone Miner Res ; 38(12): 1822-1833, 2023 12.
Article in English | MEDLINE | ID: mdl-37823782

ABSTRACT

Cherubism is a rare autosomal dominant disease characterized by expansile osteolytic jawbone lesions. The effect and safety of off-label calcitonin treatment during the progressive phase of the disease are not well described. In this retrospective study, we present data on the radiological response and adverse effects of subcutaneously administered calcitonin in a cohort of nine cherubism children (three female, six male). Two of the nine patients underwent two separate treatment courses with a significant off-treatment interval in between; therefore, a total of 11 treatment courses with a mean duration of 17.9 months (range <1 to 35, SD 10.8) were studied. To measure the response, the cumulative volume of cherubism lesions was calculated from available three-dimensional imaging. The primary outcome was the change in the volume of lesions during calcitonin treatment and only assessed for the eight treatment courses with a minimal duration of 6 months. A statistically significant reduction in the mean cumulative volume of lesions was seen regardless of treatment duration. Average volume reduction was highest in the first half year of treatment, with a gradual, ongoing reduction thereafter. For the secondary outcome, the change in the cumulative volume of lesions after treatment cessation was assessed for the seven treatment courses with follow-up imaging available. After six of these seven treatment courses, the cumulative volume increased again but remained undoubtedly smaller than the initial volume at the start of therapy. Adverse effects were assessed for all 11 treatment courses and occurred in 73% of them. Most adverse effects were mild and low grade, with the most severe being one grade 3 symptomatic hypocalcemia requiring hospitalization and early treatment termination. Calcitonin treatment seems effective and tolerable in treating actively progressing cherubism in children. However, further research is required to better understand the pharmacological treatment of cherubism, including also other drugs, dosing, and protocols. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).


Subject(s)
Calcitonin , Cherubism , Child , Humans , Male , Female , Calcitonin/adverse effects , Cohort Studies , Cherubism/drug therapy , Retrospective Studies , Minerals
2.
Clin Kidney J ; 16(3): 456-472, 2023 Mar.
Article in English | MEDLINE | ID: mdl-36865010

ABSTRACT

The coexistence of osteoporosis and chronic kidney disease (CKD) is an evolving healthcare challenge in the face of increasingly aging populations. Globally, accelerating fracture incidence causes disability, impaired quality of life and increased mortality. Consequently, several novel diagnostic and therapeutic tools have been introduced for treatment and prevention of fragility fractures. Despite an especially high fracture risk in CKD, these patients are commonly excluded from interventional trials and clinical guidelines. While management of fracture risk in CKD has been discussed in recent opinion-based reviews and consensus papers in the nephrology literature, many patients with CKD stages 3-5D and osteoporosis are still underdiagnosed and untreated. The current review addresses this potential treatment nihilism by discussing established and novel approaches to diagnosis and prevention of fracture risk in patients with CKD stages 3-5D. Skeletal disorders are common in CKD. A wide variety of underlying pathophysiological processes have been identified, including premature aging, chronic wasting, and disturbances in vitamin D and mineral metabolism, which may impact bone fragility beyond established osteoporosis. We discuss current and emerging concepts of CKD-mineral and bone disorders (CKD-MBD) and integrate management of osteoporosis in CKD with current recommendations for management of CKD-MBD. While many diagnostic and therapeutic approaches to osteoporosis can be applied to patients with CKD, some limitations and caveats need to be considered. Consequently, clinical trials are needed that specifically study fracture prevention strategies in patients with CKD stages 3-5D.

3.
Transpl Int ; 35: 10330, 2022.
Article in English | MEDLINE | ID: mdl-36157271

ABSTRACT

Prehabilitation improves surgical outcomes in patients undergoing surgery. However, patients preparing for orthotopic liver transplantation (OLT) are physically "frail" and suffer from comorbidities that generally hamper physical activity. This systematic review aims to evaluate the physical effects, safety and feasibility of prehabilitation in OLT candidates. Relevant articles were searched, in Embase, Web of Science, Cochrane, Medline and Google Scholar, to December 2021. Studies reporting on specified preoperative exercise programs, including adult OLT candidates with end-stage liver disease, with a model for end-stage liver disease (MELD) score ≥12 or Child-Pugh classification B/C, were included. This resulted in 563 potentially eligible studies, out of which eight were selected for inclusion, consisting of 1,094 patients (male sex 68%; mean age 51-61 years; mean MELD score 12-21). Six of the included studies were classified as low-quality by the GRADE system, and three studies had high risk for ineffectiveness of the training program according to the i-CONTENT tool. Significant improvement was observed in VO2 peak, 6-minute walking distance, hand grip strength, liver frailty index and quality of life. Feasibility ranged from an adherence of 38%-90% in unsupervised-to >94% in supervised programs. No serious adverse events were reported. In conclusion, prehabilitation in patients awaiting OLT appears to improve aerobic capacity, and seems feasible and safe. However, larger clinical trials are required to accurately examine the preoperative and postoperative effects of prehabilitation in this specific patient population.


Subject(s)
End Stage Liver Disease , Liver Transplantation , Adult , End Stage Liver Disease/surgery , Feasibility Studies , Hand Strength , Humans , Male , Middle Aged , Postoperative Complications/prevention & control , Preoperative Care/methods , Preoperative Exercise , Quality of Life , Severity of Illness Index
4.
Ann Surg ; 276(2): 239-245, 2022 08 01.
Article in English | MEDLINE | ID: mdl-36036990

ABSTRACT

OBJECTIVE: The effects of intraoperative blood salvage (IBS) on time to tumor recurrence, disease-free survival and overall survival in hepatocellular carcinoma (HCC) patients undergoing liver transplantation were assessed to evaluate the safety of IBS. BACKGROUND: IBS is highly effective to reduce the use of allogeneic blood transfusion. However, the safety of IBS during liver transplantation for patients with HCC is questioned due to fear of disseminating malignant cells. METHODS: Comprehensive searches through June 2021 were performed in 8 databases. The methodological quality of included studies was assessed using the Robins-I tool. Meta-analysis with the generic inverse variance method was performed to calculate pooled hazard ratios (HRs) for disease-free survival, HCC recurrence and overall survival. RESULTS: Nine studies were included (n=1997, IBS n=1200, no-IBS n=797). Use of IBS during liver transplantation was not associated with impaired disease-free survival [HR=0.90, 95% confidence interval (CI)=0.66-1.24, P=0.53, IBS n=394, no-IBS n=329], not associated with increased HCC recurrence (HR=0.83, 95% CI=0.57-1.23, P=0.36, IBS n=537, no-IBS n=382) and not associated with impaired overall survival (HR=1.04, 95% CI=0.79-1.37, P=0.76, IBS n=495, no-IBS n=356). CONCLUSIONS: Based on available observational data, use of IBS during liver transplantation in patients with HCC does not result in impaired disease-free survival, increased HCC recurrence or impaired overall survival. Therefore, use of IBS during liver transplantation for HCC patients is a safe procedure.


Subject(s)
Carcinoma, Hepatocellular , Liver Neoplasms , Liver Transplantation , Operative Blood Salvage , Carcinoma, Hepatocellular/surgery , Humans , Liver Neoplasms/surgery , Neoplasm Recurrence, Local , Retrospective Studies
5.
Anaesthesiol Intensive Ther ; 53(2): 103-107, 2021.
Article in English | MEDLINE | ID: mdl-34006050

ABSTRACT

INTRODUCTION: Percutaneous measurement of haemoglobin (SpHb) has been an emerging technique in the past decades. It has been suggested that SpHb measurement could be used as a trend monitor and as a supportive tool for easier and faster transfusion decision-making. The aim of this study was to investigate whether SpHb monitoring is a useful instrument in transfusion decision-making. MATERIAL AND METHODS: Patients scheduled for surgery with expected blood loss over 800 mL were included in the study. SpHb was measured using a Masimo Rainbow probe. Blood samples were drawn before and after surgery and, if clinically indicated, during surgery. Moreover, perfusion parameters were analysed, as well as transfusion triggers. RESULTS: Based on transfusion triggers 27.1% of patients would not have been transfused according to National Guidelines (14.5% transfused in error, 12.5% not transfused when indicated). Invasive haemoglobin (invasive Hb) and SpHb were obtained 266 times in 75 patients. The mean invasive Hb was 7.37 ± 1.34 mmol L-1 and SpHb was 6.47 ± 0.81 mmol L-1 (P < 0.001). Bland-Altman analysis corrected for multiple measurements revealed proportional bias of -4.05 + 0.72 Hb (least bias at Hb 5.62). CONCLUSIONS: The precision of the SpHb measurement exceeded the acceptable range of error. We concluded that SpHb measurement using the Rainbow device is too unreliable to be an acceptable alternative to invasive Hb measurement, or even as a trend monitor or decision support tool.


Subject(s)
Blood Transfusion , Monitoring, Intraoperative , Hemoglobins/analysis , Humans , Monitoring, Physiologic , Oximetry , Prospective Studies
6.
J Cell Mol Med ; 19(11): 2655-63, 2015 Nov.
Article in English | MEDLINE | ID: mdl-26282710

ABSTRACT

Reperfusion injury following myocardial infarction (MI) increases infarct size (IS) and deteriorates cardiac function. Cardioprotective strategies in large animal MI models often failed in clinical trials, suggesting translational failure. Experimentally, MI is induced artificially and the effect of the experimental procedures may influence outcome and thus clinical applicability. The aim of this study was to investigate if invasive surgery, as in the common open chest MI model affects IS and cardiac function. Twenty female landrace pigs were subjected to MI by transluminal balloon occlusion. In 10 of 20 pigs, balloon occlusion was preceded by invasive surgery (medial sternotomy). After 72 hrs, pigs were subjected to echocardiography and Evans blue/triphenyl tetrazoliumchloride double staining to determine IS and area at risk. Quantification of IS showed a significant IS reduction in the open chest group compared to the closed chest group (IS versus area at risk: 50.9 ± 5.4% versus 69.9 ± 3.4%, P = 0.007). End systolic LV volume and LV ejection fraction measured by echocardiography at follow-up differed significantly between both groups (51 ± 5 ml versus 65 ± 3 ml, P = 0.033; 47.5 ± 2.6% versus 38.8 ± 1.2%, P = 0.005). The inflammatory response in the damaged myocardium did not differ between groups. This study indicates that invasive surgery reduces IS and preserves cardiac function in a porcine MI model. Future studies need to elucidate the effect of infarct induction technique on the efficacy of pharmacological therapies in large animal cardioprotection studies.


Subject(s)
Myocardial Infarction/surgery , Animals , Disease Models, Animal , Echocardiography , Female , Heart/physiopathology , Myocardial Infarction/physiopathology , Myocardial Reperfusion Injury , Myocardium/pathology , Recovery of Function , Swine
7.
Biomed Res Int ; 2015: 209315, 2015.
Article in English | MEDLINE | ID: mdl-25802838

ABSTRACT

BACKGROUND: Novel therapies need to be evaluated in a relevant large animal model that mimics the clinical course and treatment in a reasonable time frame. To reliably assess therapeutic efficacy, knowledge regarding the translational model and the course of disease is needed. METHODS: Landrace pigs were subjected to a transient occlusion of the proximal left circumflex artery (LCx) (n = 6) or mid-left anterior descending artery (LAD) (n = 6) for 150 min. Cardiac function was evaluated before by 2D echocardiography or 3D echocardiography and pressure-volume loop analysis. At 12 weeks of follow-up the heart was excised for histological analysis and infarct size calculations. RESULTS: Directly following AMI, LVEF was severely reduced compared to baseline in the LAD group (-17.1 ± 1.6%, P = 0.009) compared to only a moderate reduction in the LCx group (-5.9 ± 1.5%, P = 0.02) and this effect remained unchanged during 12 weeks of follow-up. CONCLUSION: Two models of chronic MI, representative for different patient groups, can reproducibly be created through clinically relevant ischemia-reperfusion of the mid-LAD and proximal LCx.


Subject(s)
Heart/physiopathology , Myocardial Infarction/physiopathology , Animals , Disease Models, Animal , Echocardiography/methods , Echocardiography, Three-Dimensional/methods , Female , Follow-Up Studies , Swine
8.
Circ Cardiovasc Interv ; 7(5): 673-83, 2014 Oct.
Article in English | MEDLINE | ID: mdl-25294400

ABSTRACT

BACKGROUND: Engraftment and survival of stem cells in the infarcted myocardium remain problematic in cell-based therapy for cardiovascular disease. To overcome these issues, encapsulated mesenchymal stem cells (eMSCs) were developed that were transfected to produce glucagon-like peptide-1, an incretin hormone with known cardioprotective effects, alongside MSC endogenous paracrine factors. This study was designed to investigate the efficacy of different doses of intracoronary infusion of eMSC in a porcine model of acute myocardial infarction (AMI). METHODS AND RESULTS: One hundred pigs were subjected to a moderate AMI (posterolateral AMI; n=50) or a severe AMI (anterior AMI; n=50), whereupon surviving animals (n=36 moderate, n=33 severe) were randomized to receive either intracoronary infusion of 3 incremental doses of eMSC or Ringers' lactate control. Cardiac function was assessed using invasive hemodynamics, echocardiography, and histological analysis. A trend was observed in the moderate AMI model, whereas in the severe AMI model, left ventricular ejection fraction improved by +9.3% (P=0.004) in the best responding eMSC group, because of a preservation of left ventricular end-systolic volume. Arteriolar density increased 3-fold in the infarct area (8.4±0.9/mm(2) in controls versus 22.2±2.6/mm(2) in eMSC group; P<0.001). Although not statistically significant, capillary density was 30% higher in the border zone (908.1±99.7/mm(2) in control versus 1209.0±64.6/mm(2) in eMSC group; P=ns). CONCLUSIONS: eMSCs enable sustained local delivery of cardioprotective proteins to the heart, thereby enhancing angiogenesis and preserving contractile function in an animal AMI model.


Subject(s)
Glucagon-Like Peptide 1/metabolism , Mesenchymal Stem Cell Transplantation/methods , Mesenchymal Stem Cells/metabolism , Myocardial Infarction/therapy , Myocardium/pathology , Animals , Coronary Vessels/surgery , Disease Models, Animal , Echocardiography , Glucagon-Like Peptide 1/genetics , Humans , Infusions, Intra-Arterial , Swine , Transgenes/genetics , Ventricular Function, Left
9.
Circ Cardiovasc Interv ; 7(2): 156-67, 2014 Apr.
Article in English | MEDLINE | ID: mdl-24668227

ABSTRACT

BACKGROUND: Several cell-based therapies for adjunctive treatment of acute myocardial infarction have been investigated in multiple clinical trials, but the benefits still remain controversial. This meta-analysis aims to evaluate the efficacy of bone marrow-derived mononuclear cell (BMMNC) therapy in patients with acute myocardial infarction, but also explores the effect of newer generations of stem cells. METHODS AND RESULTS: A random-effects meta-analysis was performed on randomized controlled trials investigating the effects of stem cell therapy in patients with acute myocardial infarction that were published between January 2002 and September 2013. The defined end points were left ventricular (LV) ejection fraction, LV end-systolic and end-diastolic volumes, infarct size, and major adverse cardiac and cerebrovascular event rates. Also, several subgroup analyses were performed on BMMNC trials. Overall, combining the results of 22 randomized controlled trials (RCTs), LV ejection fraction increased by +2.10% (95% confidence interval [CI], 0.68-3.52; P=0.004) in the BMMNC group as compared with controls, evoked by a preservation of LV end-systolic volume (-4.05 mL; 95% CI, -6.91 to -1.18; P=0.006) and a reduction in infarct size (-2.69%; 95% CI, -4.83 to -0.56; P=0.01). However, there is no effect on cardiac function, volumes, or infarct size, when only RCTs (n=9) that used MRI-derived end points were analyzed. Moreover, no beneficial effect could be detected on major adverse cardiac and cerebrovascular event rates after BMMNC infusion after a median follow-up duration of 6 months. CONCLUSIONS: Intracoronary infusion of BMMNC is safe, but does not enhance cardiac function on MRI-derived parameters, nor does it improve clinical outcome. New and possibly more potent stem cells are emerging in the field, but their clinical efficacy still needs to be defined in future trials.


Subject(s)
Cell- and Tissue-Based Therapy/methods , Infusions, Intra-Arterial/methods , Myocardial Infarction/therapy , Stem Cell Transplantation/methods , Follow-Up Studies , Humans , Hypertrophy, Left Ventricular/pathology , Infusions, Intra-Arterial/adverse effects , Magnetic Resonance Imaging , Myocardial Infarction/pathology , Myocardial Infarction/physiopathology , Randomized Controlled Trials as Topic , Stem Cell Transplantation/adverse effects , Stroke Volume/physiology , Treatment Outcome
10.
Cell Transplant ; 23(12): 1525-35, 2014.
Article in English | MEDLINE | ID: mdl-23561893

ABSTRACT

The objective of this study was to assess the effect of high-dose atorvastatin treatment on endothelial progenitor cell (EPC) recruitment and angiographic and clinical outcome in coronary artery disease (CAD) patients treated with the Genous EPC-capturing stent. The HEALING IIB study was a multicenter, open-label, prospective trial that enrolled 100 patients. Patients were started on 80 mg atorvastatin qd, at least 2 weeks before the index procedure and continued for at least 4 weeks after the index procedure. Eighty-seven patients were included in this analysis. EPC levels significantly increased as early as 2 weeks after the start of atorvastatin. Remarkably, among this group, 31 patients proved to be nonresponders to atorvastatin treatment (i.e., no increase in EPC levels), while 56 patients were responders (i.e., rise in EPC count between week -2 and 0). Compared to responders, nonresponders had a significantly higher baseline EPC count (76 ± 10 vs. 41 ± 5, p < 0.01) with a lower late luminal loss (LLL) at 6- and 18-month follow-up (FU) (0.61 ± 0.07 vs. 0.88 ± 0.08, p < 0.05, and 0.50 ± 0.08 vs. 0.82 ± 0.08, p < 0.01 respectively). Furthermore, baseline EPC count was inversely correlated with LLL at 6-month FU (R = -0.42, p < 0.001). Patients with a higher EPC count at baseline showed no increase in EPC recruitment in response to statin treatment but had favorable LLL at 6- and 18-month FU, whereas patients with lower EPC count were responsive to statin therapy, but EPCs might be less functional as they had higher LLL at 6- and 18-month FU. These data imply that although statin treatment can enhance EPC titer in patients with low baseline levels, there is no indication for a possible beneficial clinical effect with EPC capture stents.


Subject(s)
Coronary Angiography , Coronary Artery Disease/diagnostic imaging , Coronary Artery Disease/pathology , Endothelial Progenitor Cells/drug effects , Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology , Stents , Adult , Aged , Aged, 80 and over , Atorvastatin , Coronary Artery Disease/blood , Demography , Female , Heptanoic Acids/pharmacology , Humans , Lipids/blood , Male , Middle Aged , Multivariate Analysis , Pyrroles/pharmacology , Regression Analysis , Treatment Outcome
11.
Methods Mol Biol ; 1036: 207-12, 2013.
Article in English | MEDLINE | ID: mdl-23807797

ABSTRACT

Adipose tissue represents an abundant, accessible source of regenerative cells that can be easily obtained in sufficient amount for therapy. Adipose-derived regenerative cells (ADRC) are comprised of leukocytes, smooth muscles, endothelial cells, and mesenchymal stem cells. In contrast to bone-marrow-derived MSC, the abundance of adipose tissue in patients and the higher frequency per unit mass of regenerative cells allow for the isolation of cells in therapeutic meaningful amounts in less than 2h after donor tissue acquisition.Harvest of adipose tissue can thus follow primary PCI, allowing efficient treatment within 24h. This obviates the need for extensive cell culturing in GMP clean room facilities and makes ADSCs a promising and practical autologous cell source. In the following chapter, we will describe the liposuction procedure for stem cell harvest, two cell delivery techniques, and pressure/volume loop analysis for the follow-up of our patients enrolled in the clinical studies.


Subject(s)
Adipose Tissue/transplantation , Cell Separation/methods , Heart Failure/therapy , Lipectomy/methods , Mesenchymal Stem Cell Transplantation/methods , Mesenchymal Stem Cells/cytology , Myocardial Infarction/therapy , Acute Disease , Cell Differentiation , Cells, Cultured , Clinical Trials as Topic , Humans
12.
Circ Res ; 113(2): 153-66, 2013 Jul 05.
Article in English | MEDLINE | ID: mdl-23658436

ABSTRACT

RATIONALE: Mesenchymal precursor cells (MPCs) are a specific Stro-3+ subpopulation of mesenchymal stem cells isolated from bone marrow. MPCs exert extensive cardioprotective effects, and are considered to be immune privileged. OBJECTIVE: This study assessed the safety, feasibility, and efficacy of intracoronary delivery of allogeneic MPCs directly after acute myocardial infarction in sheep. METHODS AND RESULTS: Initially, intracoronary delivery conditions were optimized in 20 sheep. These conditions were applied in a randomized study of 68 sheep with an anterior acute myocardial infarction. Coronary flow was monitored during MPC infusion, and cardiac function was assessed using invasive hemodynamics and echocardiography at baseline and during 8 weeks follow-up. Coronary flow remained within thrombolysis in myocardial infarction III definitions in all sheep during MPC infusion. Global left ventricular ejection fraction as measured by pressure-volume loop analysis deteriorated in controls to 40.7±2.6% after 8 weeks. In contrast, MPC treatment improved cardiac function to 52.8±0.7%. Echocardiography revealed significant improvement of both global and regional cardiac functions. Infarct size decreased by 40% in treated sheep, whereas infarct and border zone thickness were enhanced. Left ventricular adverse remodeling was abrogated by MPC therapy, resulting in a marked reduction of left ventricular volumes. Blood vessel density increased by >50% in the infarct and border areas. Compensatory cardiomyocyte hypertrophy was reduced in border and remote segments, accompanied by reduced collagen deposition and apoptosis. No microinfarctions in remote myocardial segments or histological abnormalities in unrelated organs were found. CONCLUSIONS: Intracoronary infusion of allogeneic MPCs is safe, feasible, and markedly effective in a large animal model of acute myocardial infarction.


Subject(s)
Coronary Vessels/physiology , Mesenchymal Stem Cell Transplantation/methods , Myocardial Infarction/pathology , Myocardial Infarction/surgery , Ventricular Function, Left/physiology , Ventricular Remodeling/physiology , Animals , Follow-Up Studies , Infusions, Intra-Arterial , Myocardial Infarction/physiopathology , Random Allocation , Sheep , Transplantation, Homologous
13.
Cell Transplant ; 22(3): 535-43, 2013.
Article in English | MEDLINE | ID: mdl-22507673

ABSTRACT

Cell therapy is a field of growing interest in the prevention of post acute myocardial infarction (AMI) heart failure. Stem cell retention upon local delivery to the heart, however, is still unsatisfactory. CellBeads were recently developed as a potential solution to this problem. CellBeads are 170-µm alginate microspheres that contain mesenchymal stem cells (MSCs) genetically modified to express glucagon-like peptide-1 (GLP-1) supplementary to inherent paracrine factors. GLP-1 is an incretin hormone that has both antiapoptotic and cardioprotective effects. Transplanting CellBeads in the post-AMI heart might induce cardiomyocyte salvage and ultimately abrogate adverse cardiac remodeling. We aimed to investigate the feasibility of intracoronary infusion of CellBeads in a large animal model of AMI. Four pigs were used in a pilot study to assess the maximal safe dose of CellBeads. In the remaining 21 animals, an AMI was induced by balloon occlusion of the left circumflex coronary artery for 90 min. During reperfusion, 60,000 CellBeads (n = 11), control beads (n = 4), or lactated Ringers' (n = 6) were infused. Animals were sacrificed after 2 or 7 days, and the hearts were excised for histological analyses. Intracoronary infusion did not permanently affect coronary flow in any of the groups. Histological analysis revealed CellBeads containing viable MSCs up to 7 days. Viability and activity of the MSCs was confirmed by qPCR analysis that showed expression of recombinant GLP-1 and human genes after 2 and 7 days. CellBeads reduced inflammatory infiltration by 29% (p = 0.001). In addition, they decreased the extent of apoptosis by 25% (p = 0.001) after 2 days. We show that intracoronary infusion of 5 million encapsulated MSCs is safe and feasible. Also, several parameters indicate that the cells have paracrine effects, suggesting a potential therapeutic benefit of this new approach.


Subject(s)
Glucagon-Like Peptide 1/metabolism , Mesenchymal Stem Cell Transplantation/methods , Myocardial Infarction/therapy , Acute Disease , Alginates/chemistry , Animals , Apoptosis , Balloon Occlusion , Cell- and Tissue-Based Therapy , Female , Glucagon-Like Peptide 1/genetics , Glucuronic Acid/chemistry , Hexuronic Acids/chemistry , Humans , Mesenchymal Stem Cells/cytology , Mesenchymal Stem Cells/metabolism , Myocardial Infarction/pathology , Myocardium/metabolism , Myocardium/pathology , Myocytes, Cardiac/cytology , Pilot Projects , Swine
14.
Circulation ; 125(25): 3142-58, 2012 Jun 26.
Article in English | MEDLINE | ID: mdl-22661514

ABSTRACT

BACKGROUND: New vessel formation contributes to organ development during embryogenesis and tissue repair in response to mechanical damage, inflammation, and ischemia in adult organisms. Early angiogenesis includes formation of an excessive primitive network that needs to be reorganized into a secondary vascular network with higher hierarchical structure. Vascular pruning, the removal of aberrant neovessels by apoptosis, is a vital step in this process. Although multiple molecular pathways for early angiogenesis have been identified, little is known about the genetic regulators of secondary network development. METHODS AND RESULTS: Using a transcriptomics approach, we identified a new endothelial specific gene named FYVE, RhoGEF, and PH domain-containing 5 (FGD5) that plays a crucial role in vascular pruning. Loss- and gain-of-function studies demonstrate that FGD5 inhibits neovascularization, indicated by in vitro tube-formation, aortic-ring, and coated-bead assays and by in vivo coated-bead plug assays and studies in the murine retina model. FGD5 promotes apoptosis-induced vaso-obliteration via induction of the hey1-p53 pathway by direct binding and activation of cdc42. Indeed, FGD5 correlates with apoptosis in endothelial cells during vascular remodeling and was linked to rising p21(CIP1) levels in aging mice. CONCLUSION: We have identified FGD5 as a novel genetic regulator of vascular pruning by activation of endothelial cell-targeted apoptosis.


Subject(s)
Apoptosis Regulatory Proteins/physiology , Endothelium, Vascular/pathology , Guanine Nucleotide Exchange Factors/physiology , Human Umbilical Vein Endothelial Cells/pathology , Neovascularization, Pathologic/pathology , Neovascularization, Pathologic/prevention & control , Animals , Apoptosis Regulatory Proteins/genetics , Cell Proliferation , Cells, Cultured , Endothelium, Vascular/metabolism , Guanine Nucleotide Exchange Factors/genetics , Human Umbilical Vein Endothelial Cells/metabolism , Humans , Mice , Mice, Inbred C57BL , Mice, SCID , Neovascularization, Pathologic/genetics , Retinal Diseases/genetics , Retinal Diseases/metabolism , Retinal Diseases/pathology , Transcriptome/genetics
15.
Circ Cardiovasc Interv ; 5(2): 279-87, 2012 Apr.
Article in English | MEDLINE | ID: mdl-22354933

ABSTRACT

BACKGROUND: Toll-like receptor (TLR)-2 is an important mediator of innate immunity and ischemia/reperfusion-induced cardiac injury. We have previously shown that TLR2 inhibition reduces infarct size and improves cardiac function in mice. However, the therapeutic efficacy of a clinical grade humanized anti-TLR2 antibody, OPN-305, in a large-animal model remained to be addressed. METHODS AND RESULTS: Pigs (n=38) underwent 75 minutes ischemia followed by 24 hours of reperfusion. Saline or OPN-305 (12.5, 6.25, or 1.56 mg/kg) was infused intravenously 15 minutes before reperfusion. Cardiac function and geometry were assessed by echocardiography. Infarct size was calculated as the percentage of the area at risk and by serum Troponin-I levels. Flow cytometry analysis revealed specific binding of OPN-305 to porcine TLR2. In vivo, OPN-305 exhibited a secondary half-life of 8±2 days. Intravenous administration of OPN-305 before reperfusion significantly reduced infarct size (45% reduction, P=0.041) in a dose-dependent manner. In addition, pigs treated with OPN-305 exhibited a significant preservation of systolic performance in a dose-dependent fashion, whereas saline treatment completely diminished the contractile performance of the ischemic/reperfused myocardium. CONCLUSIONS: OPN-305 significantly reduces infarct size and preserves cardiac function in pigs after ischemia/reperfusion injury. Hence, OPN-305 is a promising adjunctive therapeutic for patients with acute myocardial infarction.


Subject(s)
Antibodies, Monoclonal, Humanized/administration & dosage , Heart/drug effects , Myocardial Infarction/drug therapy , Myocardium/metabolism , Reperfusion Injury/prevention & control , Toll-Like Receptor 2/immunology , Animals , Antibodies, Monoclonal, Humanized/adverse effects , Antibodies, Monoclonal, Humanized/pharmacokinetics , Chemotherapy, Adjuvant/trends , Disease Models, Animal , Echocardiography , Female , Half-Life , Heart/physiopathology , Humans , Immunity, Innate , Infusions, Intravenous , Mice , Myocardial Contraction/drug effects , Myocardial Infarction/complications , Myocardial Infarction/pathology , Myocardial Infarction/physiopathology , Myocardium/immunology , Myocardium/pathology , Protein Binding/drug effects , Reperfusion Injury/etiology , Reperfusion Injury/pathology , Reperfusion Injury/physiopathology , Swine , Toll-Like Receptor 2/antagonists & inhibitors
17.
Eur Heart J ; 33(1): 120-8, 2012 Jan.
Article in English | MEDLINE | ID: mdl-21733913

ABSTRACT

AIMS: The Genous™ Bio-engineered R™ stent (GS) aims to promote vascular healing by capture of circulatory endothelial progenitor cells (EPCs) to the surface of the stent struts, resulting in accelerated re-endothelialization. Here, we assessed the function of the GS in comparison to bare-metal stent (BMS), when exposed to the human and animal circulation. METHODS AND RESULTS: First, 15 patients undergoing coronary angiography received an extracorporeal femoral arteriovenous (AV) shunt containing BMS and GS. Macroscopical mural thrombi were observed in BMS, whereas GS remained visibly clean. Confocal and scanning electron microscopic (SEM) analysis of GS showed an increase in strut coverage. Quantitative polymerase chain reaction (qPCR) analysis of captured cells on the GS demonstrated increased expression of endothelial markers KDR/VEGFR2 and E-selectin, and a decrease in pro-thrombogenic markers tissue factor pathway inhibitor and plasminogen activator inhibitor-1 compared with BMS. Secondly, a similar primate AV shunt model was used to validate these findings and occlusion of BMS was observed, while GS remained patent, as demonstrated by live imaging of indium-labelled platelets. Thirdly, in an in vitro cell-capture assay, GS struts showed increased coverage by EPCs, whereas monocyte coverage remained similar to BMS. Finally, the assessment of re-endothelialization was studied in a rabbit denudation model. Twenty animals received BMS and GS in the aorta and iliac arteries for 7 days. Scanning electron microscopic analysis showed a trend towards increased strut coverage, confirmed by qPCR analysis revealing increased levels of endothelial markers (Tie2, CD34, PCD31, and P-selectin) in GS. CONCLUSION: In this proof-of-concept study, we have demonstrated that the bio-engineered EPC-capture stent, Genous™ R™ stent, is effective in EPC capture, resulting in accelerated re-endothelialization and reduced thrombogenicity.


Subject(s)
Arteriovenous Shunt, Surgical/methods , Bioengineering , Coronary Artery Disease/therapy , Endothelial Cells/physiology , Stem Cells/physiology , Stents , Aged , Angioplasty, Balloon, Coronary/methods , Animals , Antigens, CD34/metabolism , Biomarkers/metabolism , Cardiac Catheterization/methods , Coronary Restenosis/prevention & control , Cytokines/metabolism , Disease Models, Animal , Endothelium, Vascular/cytology , Female , Graft Occlusion, Vascular/prevention & control , Humans , Leukocytes, Mononuclear/physiology , Male , Microscopy, Electron , Middle Aged , Papio , Platelet Adhesiveness/physiology , Rabbits
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