CD34+CXCR4+ Cell Therapy (AMR-001) for Myocardial Infarction: Preliminary Processing and Product Results of a Phase I Dose Escalation Study.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 773-773
Author(s):  
Ned Waller ◽  
Arshed Quyyumi ◽  
Douglas Vaughan ◽  
Thomas Moss ◽  
Wai S. Chan ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Bone Marrow ◽  
Cell Death ◽  
Phase I ◽  
Ventricular Remodeling ◽  
Phase 1 ◽  
Myocardial Cell ◽  
Infarct Zone ◽  
St Segment ◽  
Cd34 Cells

Abstract Background: Approximately 20% of patients suffering a ST segment elevated acute myocardial infarction (AMI) have progressive peri-infarct zone myocardial cell death causing ventricular remodeling and poor cardiac outcomes in spite of large vessel revascularization and medical management. Neo-angiogenesis occurs when VEGF levels peak and endothelial precursors are mobilized and recruited to the infarct site. Stromal cell derived factor-1 (SDF-1), the ligand for the CXCR4 receptor, is expressed by CD34+ cells and plays a role in cell homing to areas of ischemic damage. CD34+ CXCR4+ cells home to areas of ischemia, rich in SDF-1, including infarcted myocardium and are capable of inducing neo-angiogenesis. Natural neoangiogenesis is present but insufficient following AMI, suggesting that direct administration of CD34+ CXCR4+ progenitors could mitigate peri-infarct zone myocardial cell death and improve ventricular function. Methods: In this phase I study, patients with an ST segment (AMI) are enrolled in cohorts of 5 to receive one of four doses (5, 10, 15, 20 x 106 of bone marrow derived CD34+ cells. Cells are harvested using a mini-bone marrow harvest (MMH) technique, acquired by Isolex selection and administered by infusion via the infarct related artery 5 to 10 day following successful coronary artery stenting post AMI. The first 10 subjects accrued as subjects on this phase 1 study included 9 males and 1 female, with a median age of 52 years (range 36–70). Results: The first ten patients (of 20 planned) underwent a MMH under conscious sedation without incident. Adequate numbers of viable, enriched CD34+ cells were obtained following Isolex selection for treatment of subjects enrolled at the first two dose cohorts (5 x 106 and 10 x 106 CD34+ cells). The mean fraction of cells expressing CD34 in the marrow product was 0.75%, with a mean recovery of 40% following Isolex selection (Table). Conclusions: Our study demonstrates the feasibility of collecting up to 409 ml of bone marrow using a MMH technique in the immediate post AMI setting, with yields up to 86 x 106 CD34+ cells. All patient cells expressed CXCR4 and had in vitro migratory capacity. However the lower than expected percentage of TNC expressing CD34 (compared with 9 healthy age matched individuals (1.49% vs. 0.75%) and a low % recovery following Isolex selection may limit successful upper (>10 x 106) cohort treatments. VEGf-2 expression on enriched CD34+ cells was variable. Processing and Product Results (N=10) mean (median) range *N=7 (technical loss of 3 samples);** N=9 (technical loss of 1 sample) MMH marrow volume (ml) 395 (396) 377 – 409 Harvest TNC content (x 109) 6.65 ( 6.73) 3.85 – 8.59 Harvest CD34+ content (x 106) 45.3 (50.2) 16.9 – 86.7 Harvest CD34+ % of TNC 0.75% (0.72%) 0.54% – 1.06% Selected CD34+ content (x 106) 17.8 (16.5) 8.4 – 28.9 Selected % CD34+ recovery 40.3% (41.9%) 30.2 – 49.7 Selected %CD34+ viability 97.1% (98.0 %) 96% – 99% Selected % CD34+ purity 82.5% (84.%) 70% – 91% Total processing time (hours) 14.2 (14.0) 11 – 17 SDF-1 induced migration (% of CD34+ cells) 20.2% (17.0%) 9.5% – 35.4% CXCR-4 expression(% of CD34+ cells)* 58.7% (52.0%) 44% – 78% VEGF-2 expression (% of CD34+ cells)** 0.82% (0.86%) 0% – 2.39%

Bone Marrow Derived CD34+CXCR4+ Cells Maintain Viability, Mobility and Sterility up to 72 Hours and Are Compatible with Balloon Dilatation Catheters Used for Intra Coronary Artery Infusion; Pre-Clinical Development of a Pharmaceutical Grade Cell Therapy for Acute Myocardial Infarction (AMR-001).

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1214-1214
Author(s):  
Andrew L. Pecora ◽  
Robert A. Preti ◽  
Wai Shun Chan ◽  
Edmund K. Waller ◽  
Arshed Quyyumi ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Acute Myocardial Infarction ◽  
Bone Marrow ◽  
Coronary Artery ◽  
Cell Therapy ◽  
Balloon Dilatation ◽  
Ventricular Remodeling ◽  
Cell Loss ◽  
Infarct Zone ◽  
Cd34 Cells

Abstract Background: Approximately 20% of patients suffering a ST segment elevated acute myocardial infarction (AMI) have progressive peri-infarct zone myocardial cell death causing ventricular remodeling and poor cardiac outcomes in spite of standard medical care. Neo-angiogenesis has been proposed as a natural, albeit insufficient response to mitigate ventricular remodeling resulting from an AMI. Stromal derived growth factor-1 (SDF-1), the ligand for the CXCR4 receptor, is expressed by bone marrow derived CD34+ cells and is produced in increased quantities in the peri-infarct zone. CD34+CXCR4+ cells are the cells naturally mobilized from bone marrow following an AMI to induce neo-angiogenesis. Thus we conducted a series of pre-clinical studies to develop a pharmaceutical grade bone marrow derived cell therapy product with neo-angiogenic potential for direct intra-coronary artery infusion in patients following an AMI. Methods: Bone marrow samples were obtained from healthy volunteer donors using a mini-bone marrow harvest technique (MMH). Bone marrow was stored at 4°C for up to 24 hours then processed using Isolex (Baxter, Ill) selection to acquire CD34+ cells, formulated into a delivery apparatus and stored again at 4°C for up to an additional 48 hours in a shipping container. Following storage the cell therapy product was assessed for cell recovery, viability, sterility, CXCR-4 mobility in an SDF-1 gradient, and CFU growth before and after perfusion through the internal port of an intra-coronary artery balloon dilatation catheter. Results :13 donors (11F and 2M), with a median age of 43 years (mean 43; range 21 – 61 years) yielded a median % CD34+ cells of total nucleated cells of 1.45% (mean 1.38%; range 0.92 – 1.71%) with a higher % in males vs. females (1.67 vs.1.33%) and older (≥ 45years) vs. younger (1.49 vs.1.26%) donors. CD34+ cell viability (median 96%; range 91–98%), % CD34+ mobility in an SDF-1 gradient (11.8; 4.5–34%), CFU growth (20; 14–54) and sterility were all maintained for up to 72 hours from MMH (table). Passage of the CD34+ cells through a balloon catheter did not adversely affect any of these parameters including % mobility (at 72 hours n=3; Pre% 34, 6, 18: Post 34, 18, 23). Multiple passages (n=3) through balloon dilatation catheters did not result in significant CD34+ cell loss (median recovery 99%; range 97–111%) or loss of viability (95%; range 92–98%). Conclusion: Bone marrow derived CD34+ cells selected using the Isolex device and formulated for shipping and administration maintain for up to 72 hours a high viability, mobility in an in vitro SDF-1 gradient, CFU potential and remain sterile despite multiple passages through a balloon dilatation catheter without significant cell loss. This formulation (AMR-001) provides a pharmaceutical grade cell therapy for clinical evaluation in AMI. Median (n>3) Hours from MMH 36 hours 60 hours 72 hours Selected CD34+ cell viability % (range) 96 (95–98) 96 (91–97) 97 (91–97) Selected CD34+ mobility % 19 (11–20) 6.2 (4.5–8.8) 18 (5.7–34) CD34+ CFU (colonies) 21 (13–54) 15 (14–28) 27 (14–37)

Abstract 81: B Lymphocytes Trigger MCP3-Dependent Mobilization of Monocytes and Promote Adverse Ventricular Remodeling After Myocardial Infarction

2012 ◽  
Vol 32 (suppl_1) ◽  
Author(s):  
Yasmine Zouggari ◽  
Hafid Ait-Oufella ◽  
Philippe Bonnin ◽  
José Vilar ◽  
Coralie Guerin ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Bone Marrow ◽  
Inflammatory Response ◽  
Cardiac Function ◽  
B Cell ◽  
B Lymphocytes ◽  
Cardiac Remodeling ◽  
Ventricular Remodeling ◽  
Cell Depletion ◽  
B Cell Depletion

Leukocyte infiltration in ischemic areas is a hallmark of myocardial infarction, and persistent infiltration of innate immune cells, such as neutrophils and Ly6Chi monocytes, has been shown to promote adverse cardiac tissue remodeling. However, little is known regarding the role of mature B lymphocytes, which play a crucial role in the activation of the inflammatory response in several immune-mediated diseases. Here, we hypothesized that B lymphocytes might modulate the inflammatory response and affect the immune-dependent adverse cardiac remodeling. In a mouse model of myocardial infarction, cardiac B lymphocytes levels peaked at day 5 after the onset of infarction. Of interest, treatment with a CD20-specific monoclonal antibody decreased circulating and infiltrating B cell numbers (p=0.0008 and p=0.0002 vs control), reduced infarct size and post-ischemic immunoinflammatory response, and improved cardiac function (p=0.02 vs control) assessed by echocardiography. Intriguingly, B cell depletion was associated with an impairment of Ly6Chi monocytes mobilization from bone marrow (p=0.02 vs control), leading to reduced levels of circulating and infiltrating cardiac monocytes. The acute infarction led to transient increase of both MCP-1 and MCP-3 levels. Interestingly, B cell depletion was associated with a significant and selective reduction of MCP-3 (p=0.03 vs control) but did not alter MCP-1 levels (p=0.11). Cultured activated B cells released MCP-3 and treatment with a neutralizing MCP-3 antibody abrogated B lymphocytes-induced migration of cultured monocytes. Finally, transfer of B cell-depleted splenocytes into Rag1 -/- mice improved cardiac function after myocardial infarction compared to the transfer of non-depleted splenocytes (p=0.005). This effect was abrogated after re-supplementation with B lymphocytes isolated from wild-type mice (p=0.0007) but not from MCP-3-deficient animals (p=0.7008). In conclusion, we show that following acute myocardial infarction, B lymphocytes, trigger an MCP-3-dependent mobilization of Ly6Chi monocytes from the bone marrow to the blood, leading to their recruitment into the injured myocardium and to exacerbation of tissue inflammation, thereby promoting adverse cardiac remodeling.

Development of myocardial infarction

ESC CardioMed ◽  
2018 ◽  
pp. 1230-1232
Author(s):  
Pascal Vranckx
Keyword(s):  
Myocardial Infarction ◽  
Cell Death ◽  
Myocardial Ischaemia ◽  
Oxygen Supply ◽  
Myocardial Cell ◽  
Time Dependent ◽  
Collateral Flow ◽  
Complete Occlusion ◽  
Cell Layers ◽  
Artery Flow

Myocardial infarction is the irreversible myocardial cell death (necrosis) secondary to a prolonged lack of oxygen supply (ischaemia) caused by a complete occlusion of a major coronary in the absence of forward or collateral flow. Within the perfusion area of the occluded artery, flow deprivation and myocardial ischaemia are usually most severe subendocardially (apart from the innermost cell layers nourished from the cavity) and, at least in dogs, cell death progresses from the subendocardium to the subepicardium in a time-dependent fashion.

scholarly journals Quantitative proteomic analyses reveal that GPX4 downregulation during myocardial infarction contributes to ferroptosis in cardiomyocytes

2019 ◽  
Vol 10 (11) ◽  
Author(s):  
Tae-Jun Park ◽  
Jei Hyoung Park ◽  
Ga Seul Lee ◽  
Ji-Yoon Lee ◽  
Ji Hye Shin ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Cell Death ◽  
Lipid Peroxide ◽  
Enrichment Analysis ◽  
Underlying Mechanism ◽  
Myocardial Cell ◽  
Gene Set Enrichment Analysis ◽  
Neonatal Rat ◽  
Transcriptional Level ◽  
Regulated Necrosis

Abstract Ischaemic heart disease (IHD) is the leading cause of death worldwide. Although myocardial cell death plays a significant role in myocardial infarction (MI), its underlying mechanism remains to be elucidated. To understand the progression of MI and identify potential therapeutic targets, we performed tandem mass tag (TMT)-based quantitative proteomic analysis using an MI mouse model. Gene ontology (GO) analysis and gene set enrichment analysis (GSEA) revealed that the glutathione metabolic pathway and reactive oxygen species (ROS) pathway were significantly downregulated during MI. In particular, glutathione peroxidase 4 (GPX4), which protects cells from ferroptosis (an iron-dependent programme of regulated necrosis), was downregulated in the early and middle stages of MI. RNA-seq and qRT-PCR analyses suggested that GPX4 downregulation occurred at the transcriptional level. Depletion or inhibition of GPX4 using specific siRNA or the chemical inhibitor RSL3, respectively, resulted in the accumulation of lipid peroxide, leading to cell death by ferroptosis in H9c2 cardiomyoblasts. Although neonatal rat ventricular myocytes (NRVMs) were less sensitive to GPX4 inhibition than H9c2 cells, NRVMs rapidly underwent ferroptosis in response to GPX4 inhibition under cysteine deprivation. Our study suggests that downregulation of GPX4 during MI contributes to ferroptotic cell death in cardiomyocytes upon metabolic stress such as cysteine deprivation.

scholarly journals Orderly Process of Sequential Cytokine Stimulation Is Required for Activation and Maximal Proliferation of Primitive Human Bone Marrow CD34+ Hematopoietic Progenitor Cells Residing in G0

Blood ◽  
1997 ◽  
Vol 90 (2) ◽  
pp. 658-668 ◽  
Author(s):  
Amy C. Ladd ◽  
Robert Pyatt ◽  
Andre Gothot ◽  
Susan Rice ◽  
Jon McMahel ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Bone Marrow ◽  
Phase I ◽  
Progenitor Cells ◽  
Phase Ii ◽  
Hematopoietic Progenitor Cells ◽  
Hematopoietic Progenitor ◽  
Cd34 Cells ◽  
Cytokine Stimulation ◽  
Phase Iv

Abstract Bone marrow (BM) CD34+ cells residing in the G0 phase of cell cycle may be the most suited candidates for the examination of cell cycle activation and proliferation of primitive hematopoietic progenitor cells (HPCs). We designed a double simultaneous labeling technique using both DNA and RNA staining with Hoechst 33342 and Pyronin Y, respectively, to isolate CD34+ cells residing in G0(G0CD34+ ). Using long-term BM cultures and limiting dilution analysis, G0CD34+ cells were found to be enriched for primitive HPCs. In vitro proliferation of G0CD34+ cells in response to sequential cytokine stimulation was examined in a two-step assay. In the first step, cells received a primary stimulation consisting of either stem cell factor (SCF), Flt3-ligand (FL), interleukin-3 (IL-3), or IL-6 for 7 days. In the second step, cells from each group were washed and split into four or more groups, each of which was cultured again for another week with one of the four primary cytokines individually, or in combination. Tracking of progeny cells was accomplished by staining cells with PKH2 on day 0 and with PKH26 on day 7. Overall examination of proliferation patterns over 2 weeks showed that cells could progress into four phases of proliferation. Phase I contained cytokine nonresponsive cells that failed to proliferate. Phase II contained cells dividing up to three times within the first 7 days. Phases III and IV consisted of cells dividing up to five divisions and greater than six divisions, respectively, by the end of the 14-day period. Regardless of the cytokine used for primary stimulation, G0CD34+ cells moved only to phase II by day 7, whereas a substantial percentage of cells incubated with SCF or FL remained in phase I. Cells cultured in SCF or FL for the entire 14-day period did not progress beyond phase III but proliferated into phase IV (with <20% of cells remaining in phases I and II) if IL-3, but not IL-6, was substituted for either cytokine on day 7. G0CD34+ cells incubated with IL-3 for 14 days proliferated the most and progressed into phase IV; however, when SCF was substituted on day 7, cells failed to proliferate into phase IV. Most intriguing was a group of cells, many of which were CD34+, detected in cultures initially stimulated with IL-3, which remained as a distinct population, mostly in G0 /G1 , unable to progress out of phase II regardless of the nature of the second stimulus received on day 7. A small percentage of these cells expressed cyclin E, suggesting that their proliferation arrest may have been mediated by a cyclin-related disruption in cell cycle. These results suggest that a programmed response to sequential cytokine stimulation may be part of a control mechanism required for maintenance of proliferation of primitive HPCs and that unscheduled stimulation of CD34+ cells residing in G0 may result in disruption of cell-cycle regulation.

Treatment delay and reperfusion management of acute ST-segment elevation myocardial infarction: analysis of the China STEMI Care Project Phase 1

QJM ◽  
2020 ◽  
Author(s):  
Y Zhang ◽  
Y Tian ◽  
P Dong ◽  
Y Xu ◽  
B Yu ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Symptom Onset ◽  
Phase 1 ◽  
Coronary Intervention ◽  
Treatment Delay ◽  
Primary Pci ◽  
St Segment Elevation ◽  
Segment Elevation Myocardial Infarction ◽  
St Segment ◽  
Care Project

Summary Background The China ST-segment elevation myocardial infarction (STEMI) Care Project (CSCAP) was launched in 2011 to address the problems of insufficient reperfusion and long treatment delay in STEMI care in China. Aim To describe the baseline status of STEMI emergency care in Tertiary PCI Hospitals using Phase 1 (CSCAP-1) data. Design CSCAP-1 is a prospective multi-center STEMI registry. Methods and results A total of 4191 patients with symptom onset within 12 or 12–36 h requiring primary percutaneous coronary intervention (PCI), were enrolled from 53 tertiary PCI hospitals in 14 provinces, municipalities, and autonomous regions of China in CSCAP-1. Among them, 49.0% were self-transported to the hospital, 26.5% were transferred to the hospital by calling the emergency medical services directly, and 24.5% were transferred from other hospitals. In patients with symptom onset within 12 h, 83.2% received primary PCI, 5.9% received thrombolysis and 10.9% received conservative medications. The median door-to-balloon time was 115 (85–170) min and the median door-to-needle time for in-hospital thrombolysis was 80 (50–135) min. The overall in-hospital all-cause mortality was 2.4%, while it was 5.3% in the non-reperfusion group and 2.1% in the reperfusion group (P < 0.001). Conclusion Although a long treatment delay and a high proportion of patients transporting themselves to the hospital were observed, trends were positive with greater adoption of primary PCI and lower in-hospital mortality in tertiary hospitals in China. Our results provided important information for further integrated STEMI network construction in China.

Effects of carbon nanotube-mediated Caspase3 gene silencing on cardiomyocyte apoptosis and cardiac function during early acute myocardial infarction

Nanoscale ◽  
2020 ◽  
Vol 12 (42) ◽  
pp. 21599-21604
Author(s):  
Yi Li ◽  
Hong Yu ◽  
Liang Zhao ◽  
Yuting Zhu ◽  
Rui Bai ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Cardiac Function ◽  
Gene Silencing ◽  
Ventricular Remodeling ◽  
Myocardial Cell ◽  
Coronary Artery Ligation ◽  
Protective Effects ◽  
Sprague Dawley ◽  
Artery Ligation ◽  
Sd Rats

Caspase3 gene silencing based on the gene transfer carrier F-CNT-siCas3 had obvious protective effects on myocardial cell apoptosis, ventricular remodeling, and cardiac function in Sprague-Dawley (SD) rats after coronary artery ligation.

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