Abstract 228: Inflammasome-Primed Neutrophils Return to the Bone Marrow to Stimulate Leukocytosis Following Myocardial Infarction

2020 ◽  
Vol 127 (Suppl_1) ◽  
Author(s):  
Prabhakara R Nagareddy ◽  
Gopalkrishna Sreejit ◽  
Man K Lee ◽  
Baskaran Athmanathan ◽  
Greg A Quaife-Ryan ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Bone Marrow ◽  
Nlrp3 Inflammasome ◽  
Major Adverse Cardiovascular Events ◽  
Dependent Manner ◽  
New Paradigm ◽  
Pyrin Domain ◽  
One Year ◽  
The One ◽  
Sites Of Action

Myocardial infarction (MI) triggers myelopoiesis resulting in heightened number of neutrophils in the circulation. However, the mechanism that sustain their number and recruitment to the infarcted heart are unclear. Here, we show that in a mouse model of MI (permanent ligation of LAD), neutrophils are rapidly recruited to the infarct, where they release specific alarmins, S100A8 and S100A9. These alarmins acting either in an autocrine or paracrine manner, primed the Nod Like Receptor (NLR) family Pyrin Domain Containing 3 (Nlrp3) inflammasome in naïve neutrophils via their interaction with the Toll Like Receptor (TLR) 4. The interaction did not result in the release of IL1β systemically. However, the primed neutrophils, loaded with pro-interleukin-1β (IL-1β) returned to the bone marrow (BM) in a CXCR4 (C-X-C-motif chemokine receptor 4)- dependent manner. While at the BM, the primed-neutrophils released IL-1β through Gasdermin D pores and, stimulated granulopoiesis in a cell-autonomous manner. Strategies aimed at preventing the Nlrp3 inflammasome-priming or re-entry of the primed neutrophils to the BM dampened MI-induced granulopoiesis and markedly improved cardiac function. In subjects with acute ST-elevation myocardial infarction (STEMI), the number of neutrophils in the circulation increased both at the time of admission and following revascularization. Most importantly, patients with higher peak neutrophil counts demonstrated significantly higher incidence of major adverse cardiovascular events (MACE) during the one year follow up period. Similar to mouse data, the plasma levels of IL-1β did not change in STEMI patients at any time. However, the circulating neutrophils carried greater amounts of pro-IL-1β confirming our mouse data that granulopoiesis is likely not induced by systemic but locally delivered IL-1β by reverse migrating neutrophils. These data reveal a new paradigm of how circulatory cells establish direct communication between organs by delivering signaling molecules directly at the sites of action rather through systemically.

Retention of the NLRP3 Inflammasome-primed Neutrophils in the Bone Marrow is Essential for Myocardial Infarction-induced Granulopoiesis

Circulation ◽  
2021 ◽  
Author(s):  
Gopalkrishna Sreejit ◽  
Sunil K. Nooti ◽  
Robert M. Jaggers ◽  
Baskaran Athmanathan ◽  
Ki Ho Park ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Bone Marrow ◽  
Cardiac Function ◽  
Nlrp3 Inflammasome ◽  
Molecular Mechanisms ◽  
Elevated Serum ◽  
Serum Levels ◽  
Time Dependent ◽  
New Paradigm ◽  
Sites Of Action

Background: Acute myocardial infarction (MI) results in overzealous production and infiltration of neutrophils to the ischemic heart. This is mediated in-part by granulopoiesis induced by the S100A8/A9-NLRP3-IL-1β signaling axis in injury-exposed neutrophils. Despite the transcriptional upregulation of the NLRP3 inflammasome and associated signaling components in neutrophils, the serum levels of IL-1β, the effector molecule in granulopoiesis was not impacted by MI suggesting that IL-1β is not released systemically. We hypothesize that IL-1β is released locally within the bone marrow (BM) by inflammasome-primed and reverse-migrating neutrophils. Methods: Using a combination of time-dependent parabiosis and flow cytometry techniques, we first characterized the migration patterns of different blood cell types across the parabiotic barrier. We next induced MI in parabiotic mice by permanent ligation of the LAD artery, and examined the ability of injury-exposed neutrophils to permeate the parabiotic barrier and induce granulopoiesis in non-infarcted parabionts. Finally, utilizing multiple neutrophil adoptive and BM transplant studies, we studied the molecular mechanisms that govern reverse migration and retention of the primed neutrophils, IL-1β secretion and granulopoiesis. Cardiac function was assessed by echocardiography. Results: MI promoted greater accumulation of the inflammasome-primed neutrophils in the BM. Introducing a time-dependent parabiotic barrier to the free movement of neutrophils inhibited their ability to stimulate granulopoiesis in the non-infarcted parabionts. Prior priming of the NLRP3 inflammasome is not a prerequisite, but the presence of a functional CXCR4 (C-X-C-motif chemokine receptor 4) on the primed neutrophils and elevated serum S100A8/A9 levels are necessary for homing and retention of the reverse-migrating neutrophils. In the BM, the primed neutrophils secrete IL-1β through formation of gasdermin D pores and, promote granulopoiesis. Pharmacological and/ or genetic strategies aimed at inhibition of neutrophil homing or release of IL-1β in the BM markedly suppressed MI-induced granulopoiesis and, improved cardiac function. Conclusions: Our data reveal a new paradigm of how circulatory cells establish a direct communication between organs by delivering signaling molecules (e.g., IL-1β) directly at the sites of action rather through systemic release. We suggest that this pathway may exist to limit the off-target effects of systemic IL-1β release.

P3601Association of cdkn2b rs2891168 polymorphism with wall motion index score and the development of major adverse cardiovascular events within one year following ST elevation myocardial infarction

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
F A Magamedkerimova ◽  
F A Magamedkerimova ◽  
E N Ivantsov ◽  
N R Khasanov ◽  
E V Valeeva ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Cardiovascular Events ◽  
Wall Motion ◽  
St Elevation Myocardial Infarction ◽  
Major Adverse Cardiovascular Events ◽  
Kaplan Meier ◽  
St Elevation ◽  
One Year ◽  
The One ◽  
Cdkn2b Gene

Abstract Introduction According to the GRACE registry the largest amount of deaths occurs in the first year after ST elevation myocardial infarction (STEMI). Purpose To investigate the incidence of Major Adverse Cardiovascular Events (MACE), which include cardiovascular death, nonfatal myocardial infarction, nonfatal stroke one year after STEMI and Wall Motion Index Score (WMSI) in patients with different genotypes A/G of rs2891116 polymorphism in CDKN2B gene. Materials and methods A total of 141 patients, diagnosed with STEMI based on the Third Universal Definition of Myocardial Infarction (ESC, 2013) were included in the study, composed of 52 females and 89 males. The study group mean age was 63.8±11.8 years. Informed consent was obtained. During hospitalization echocardiography was performed and a blood sample was taken for genetic testing. Over the one-year period MACE were recorded. 17 patients were lost to follow up. Data was analysed using Kaplan-Meier estimator; to compare differences between groups log-rank test was applied; continuous data analysis was performed by Mann-Whitney test. The measured genotype frequencies fit the Hardy-Weinberg equilibrium (p>0.05). Results Kaplan-Meier survival analysis revealed that in patients with AA genotype the proportion of individuals who experienced MACE over the one year period after STEMI was higher in comparison with AG genotype carriers (log rank p=0.022). Participants with GG genotype did not show significant differences compared to other genotypes carriers (Picture 1). WMSI value in patients with AA genotype was higher (Me = 1.25; Q(0.25) = 1.13; Q(0.75) = 1.56) than in AG genotype carriers (Me = 1.13; Q(0.25) = 1.13; Q(0.75) = 1.25; p=0.037). In participants with GG genotype compared to AA and AG the WMSI value was not significantly different (Me = 1.19; Q(0.25) = 1.13; Q(0.75) = 1.32). Picture 1 Conclusions Genotype AA in CDKN2B gene rs2891168 in patients after STEMI is associated with higher probability of the development of MACE over the one year period after the index event, compared to AG genotype carriers. Participants with AA genotype exhibited a higher WMSI value after STEMI compared to patients with AG genotype.

scholarly journals Major adverse cardiovascular events after implantation of absorb bioresorbable scaffold: One-year clinical outcomes

2021 ◽  
Vol 52 (4) ◽  
pp. 249-257
Author(s):  
Tanja Šobot ◽  
Nikola Šobot ◽  
Zorislava Bajić ◽  
Nenad Ponorac ◽  
Rade Babić
Keyword(s):  
Myocardial Infarction ◽  
Clinical Outcomes ◽  
Cardiovascular Events ◽  
Major Adverse Cardiovascular Events ◽  
Timi Flow Grade ◽  
Timi Flow ◽  
Absorb Bvs ◽  
One Year ◽  
The One

Background/Aim: Bioresorbable vascular scaffold (BVS) represents a novel generation of intracoronary devices designed to be fully resorbed after healing of the stented lesion, delivering antiproliferative drug to suppress restenosis, providing adequate diameter of the coronary vessel and preserving the vascular endothelial function. It was supposed that BVS will reduce neointimal proliferation and that their late bioresorption will reduce the negative effects of traditional drug-eluting stents, including the late stent thrombosis, local vessel wall inflammation, loss of coronary vasoreactivity and the need for the long-term dual antiplatelet therapy. The purpose of this research was to investigate efficacy and safety of Absorb everolimus-eluting BVS implantation and the prevalence of major adverse cardiovascular events (MACE) at the mid-term follow-up. Methods: The study encompassed 42 patients selected for BVS implantation and fulfilling inclusion criteria - 37 male and 5 female - admitted to the Dedinje Cardiovascular Institute, Belgrade, Serbia over the one-year period (from January 2015 to January 2016) for percutaneous coronary intervention (PCI). Coronary vessel patency before and after stenting was assessed by the Thrombolysis in Myocardial Infarction flow (TIMI) grades. After the index PCI procedure with BVS all patients were clinically followed by regular (prescheduled or event-driven) visits during the next 12-month period. Results: In the intention-to-treat analysis, all Absorb BVS procedures were successful, without the need for conversion to other treatment modalities. The complete reperfusion (TIMI flow grade 3) after the intervention was established in 97.6 % of patients and 100 % of them achieved the TIMI flow grade ≥ 2. The presence of angina pectoris was reduced significantly by the BVS procedure: stable angina 57.1 % to 11.9 %, (p < 0.001) and unstable angina 31 % to 0 %, respectively (p < 0.001). After the one-year follow-up, the MACE rate was 11.9 %. Myocardial infarction occurred in 4.8 % and the need for PCI reintervention in 2.4 % of cases (not influenced by the gender or the age of patients). There were 4 cases of death (all patients were older and had lower values of left ventricular ejection fraction). Conclusion: The results of the current research demonstrated a high interventional success rate of the Absorb BVS implantation, followed by the early improvement of the anginal status. However, that was not translated into the favourable mid-term clinical outcomes, opening debate about the current status of Absorb BVS and the need for future refinements of stent design and implantation techniques.

scholarly journals Aggregated Tau-PHF6 (VQIVYK) Potentiates NLRP3 Inflammasome Expression and Autophagy in Human Microglial Cells

Cells ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 1652
Author(s):  
Chinmaya Panda ◽  
Clara Voelz ◽  
Pardes Habib ◽  
Christian Mevissen ◽  
Thomas Pufe ◽  
...  
Keyword(s):  
Tau Protein ◽  
Nlrp3 Inflammasome ◽  
Time Dependent ◽  
Microglial Cells ◽  
Inflammasome Activation ◽  
Dependent Manner ◽  
Progressive Dementia ◽  
Microglial Polarization ◽  
Protein Levels ◽  
Pyrin Domain

Intra-neuronal misfolding of monomeric tau protein to toxic β-sheet rich neurofibrillary tangles is a hallmark of Alzheimer’s disease (AD). Tau pathology correlates not only with progressive dementia but also with microglia-mediated inflammation in AD. Amyloid-beta (Aβ), another pathogenic peptide involved in AD, has been shown to activate NLRP3 inflammasome (NOD-like receptor family, pyrin domain containing 3), triggering the secretion of proinflammatory interleukin-1β (IL1β) and interleukin-18 (IL18). However, the effect of tau protein on microglia concerning inflammasome activation, microglial polarization, and autophagy is poorly understood. In this study, human microglial cells (HMC3) were stimulated with the unaggregated and aggregated forms of the tau-derived PHF6 peptide (VQIVYK). Modulation of NLRP3 inflammasome was examined by qRT-PCR, immunocytochemistry, and Western blot. We demonstrate that fibrillar aggregates of VQIVYK upregulated the NLRP3 expression at both mRNA and protein levels in a dose- and time-dependent manner, leading to increased expression of IL1β and IL18 in HMC3 cells. Aggregated PHF6-peptide also activated other related inflammation and microglial polarization markers. Furthermore, we also report a time-dependent effect of the aggregated PHF6 on BECN1 (Beclin-1) expression and autophagy. Overall, the PHF6 model system-based study may help to better understand the complex interconnections between Alzheimer’s PHF6 peptide aggregation and microglial inflammation, polarization, and autophagy.

scholarly journals Meniscus Repair Outcomes with and without Bone Marrow Aspiration Concentrate

2019 ◽  
Vol 7 (7_suppl5) ◽  
pp. 2325967119S0028 ◽  
Author(s):  
Patrick Allan Massey ◽  
Andrew Zhang ◽  
Christine Bayt Stairs ◽  
Stephen Hoge ◽  
Trevor Carroll ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Aspiration ◽  
Meniscus Repair ◽  
Control Group ◽  
Pain Level ◽  
Average Pain ◽  
The Mean ◽  
One Year ◽  
The One

Objectives: The purpose of the current study is to review the results of meniscus repairs with and without bone marrow aspiration concentrate (BMAC). It is hypothesized that with BMAC, meniscus repair outcomes will be improved when compared to without BMAC at 1 year after surgery. Methods: This is a prospective case control study performed from August 2014 until August 2017. Patients were included if they had a meniscus repair performed with no history of prior meniscus surgery to the operative knee. Patients were excluded if there was a full thickness cartilage tear or International Cartilage Repair Society (ICRS) Grade IV cartilage tear not treated in a single staged surgery. Patients were also excluded if they did not reach the one year follow-up, had a multi-ligamentous knee injury requiring multiple staged procedures. From August 2014 until November 2015, patients had meniscus repair without BMA. Menisci were all repaired arthroscopically using inside-out, outside-in and all-inside techniques. After November 2015, all meniscus repairs were augmented with BMAC. In the BMAC group, all bone marrow was obtained from the ipsilateral femur during the time of surgery. The Biocue BMAC system (Zimmer Biomet, Warsaw Indiana) was used for bone marrow aspiration and BMAC was injected directly into the tear site after repair. Numerical data such as VAS, lysholm and IKDC was analyzed using a 2 sample T-test. Categorical data such as sex, tear location, type of tear and zone of tear were analyzed using a chi-square. Results: A total of 150 patients were initially included in the study. The average age in the control group was 26.3 versus 29.4 in the BMAC group (P=0.27). Thirty seven percent of the control group had an ACL reconstruction versus 40% in the BMAC group (P= .77). The control group improved from an average pain level of 6.1 to 1.2 and the BMAC group improved from an average pain level of 5.9 to 0.7 at the 1 year end point. Both the control group and BMAC group improved with respect to pain with no difference at the 1 year end point (P=.19). There was, however a significantly larger reduction in pain at the 6 week and 3 month time point with BMAC compared to the control group (P=.02 and P=.02 respectively). At the 1-year follow-up, the mean lysholm score improved from 43 to 92 in the control group and 43 to 90 in the BMAC group. The mean IKDC score improved from 37 to 87 in the control group and 36 to 83 in the BMAC group at the one year follow-up. Conclusion: Meniscus repair outcomes were improved at 6 weeks and 3 months post-operatively, when BMAC is used to augment meniscus repair compared to repair without BMAC. Both groups, control group and BMAC meniscus repair group had improved outcomes at 1 year post-operatively with respect to VAS, lysholm and IKDC, with no difference in complication rate.

259Higher risk of myocardial infarction in the first year following 5-fluorouracil treatment

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
J W D Shanmuganathan ◽  
K H K Kragholm ◽  
B T Tayal ◽  
L P Poulsen ◽  
T C E G El-Galaly ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Chronic Obstructive ◽  
Obstructive Pulmonary Disease ◽  
Calcium Blockers ◽  
All Cause Mortality ◽  
One Year ◽  
The One ◽  
Population Controls ◽  
Age And Sex

Abstract Abstract Background 5-fluorouracil (5-FU) is the third most commonly used chemotherapeutic agent in the treatment of solid malignancies across the world. The most common manifestation of cardiotoxicity associated with 5-FU is chest pain, presenting as atypical chest pain, angina on exertion or rest and acute coronary syndromes including myocardial infarction and in worse case even death. Nevertheless, a widespread appreciation of 5-FU related cardiotoxicity including myocardial infarction is poorly understood. Purpose This study aims to examine risk of myocardial infarction in patients treated with 5-FU compared to age- and sex-matched population controls. Methods and results Methods: Individuals treated with 5-FU between 2004 and 2014 in the Danish National Patient Register were identified and risk set matching was used to find background population controls matched on age and sex in a 1:5 ratio. Furthermore, two years follow-up time were added with total 13 years. Neither 5-FU patients nor controls had prior ischemic disease. Aalen-Johansen and Kaplan-Meier estimates were used to report the cumulative incidence of myocardial infarction and all-cause mortality, respectively. A multivariable Shared Frailty Cox regression analysis (adjusted for patient age, sex, hypertension, hypercholesterolemia, diabetes, chronic obstructive pulmonary disease, chronic kidney disease, heart failure and atrial fibrillation as well as selected anti-anginal medications including nitrates, beta- and calcium-blockers) was used to determine the association between 5-FU treatment and the one-year risk of myocardial infarction. Results A total of 9,012 5-FU patients and 45,060 controls formed the study population. Differences in comorbid conditions (diabetes, chronic obstructive pulmonary disease, chronic kidney disease, heart failure and atrial fibrillation) and selected anti-anginal medications (nitrates, beta- and calcium-blockers) were non-significant (all P>0.05). The one-year cumulative incidence of myocardial infarction is significantly higher for 5-FU patients at 0.8% versus 0.6% among population controls (Figure 1A), with a competing risk of death of 25.1% versus 1.2%. The risk diminishes beyond one year and becomes lower for 5-FU patients with time (Figure 1A), along with an increasing all-cause mortality (Figure 1B). The unadjusted and adjusted hazard ratio for the one-year risk of myocardial infarction were 1.38 [95% CI 1.07–1.78] and 1.54 [95% CI 1.19–1.99]. Conclusions Although the one-year risk of myocardial infarction is higher among 5-FU patients compared with population controls, the absolute risk is small and becomes insignificant beyond one year of follow-up.

scholarly journals The One Year Incidence of Postoperative Myocardial Infarction in an Orthopedic Population

2007 ◽  
Vol 4 (1) ◽  
pp. 76-80 ◽  
Author(s):  
M. K. Urban ◽  
K. Jules-Elysee ◽  
C. Loughlin ◽  
W. Kelsey ◽  
E. Flynn
Keyword(s):  
Myocardial Infarction ◽  
Postoperative Myocardial Infarction ◽  
One Year ◽  
The One

CXCR4+ CD45− Tissue-Committed Stem Cells (TCSC) for Myocardium Reside in the Bone Marrow, Are Mobilized into the Peripheral Blood during Myocardial Infarction, and “Home” to Infarcted Myocardium in CXCR4-SDF-1 and HGF/SF-c-Met Dependent Manner.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2131-2131
Author(s):  
Magda Kucia ◽  
Buddhadeb Dawn ◽  
Yiru Guo ◽  
Greg Hunt ◽  
Marcin Wysoczynski ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Stem Cells ◽  
Bone Marrow ◽  
Peripheral Blood ◽  
Cardiac Differentiation ◽  
Specific Cell ◽  
Dependent Manner ◽  
Older Individuals ◽  
Hematopoietic Stem ◽  
Infarcted Myocardium

Abstract Several recent studies in animals as well as humans support the notion that bone marrow (BM)-derived cells participate in myocardial regeneration. However, this subject remains highly controversial and the identity of the specific cell type responsible for regeneration remains unknown. Recent work from our laboratory revealed that BM contains a highly mobile population of CXCR4+ cells that express mRNA for various markers of early tissue-committed stem cells (TCSC) and which are distinct from hematopoietic stem cells (HSC) (Leukemia2004:18;29–40). In the current study we investigated whether BM also contains a mobile pool of TCSC destined to differentiate into cardiomyocytes. Our data demonstrate that TCSC for cardiomyocytes (i) are present in significant amounts in BM harvested from young (1–2 month-old) while being barely detectable in older (1-year-old) mice; ii) reside in populations of murine BM-derived non-hematopoietic Sca-1+ CD45− cells and in population of human CXCR4+ CD34+ AC133+ CD45− BMMNC, iii) are mobilized from BM into peripheral blood (PB) during pharmacological mobilization or myocardial infarction; iv) the identified by us chemoattractants for these cells: stromal derived factor -1 (SDF-1), and hepatocyte growth factor/scatter factor (HGF/SF) are upregulated in infarcted myocardium, and v) blocking experiments with T140 (CXCR4 antagonist) and K252a (c-MET antagonist) confirmed that TCSC for cardiomyocytes are chemoattracted to the damaged myocardium in SDF-1-CXCR4 and SF/HGF-c-Met dependent manner. Thus, we conclude that the bone marrow is a potential source of TCSC for heart repair and since purified CD45+ HSC neither express cardiac markers nor differentiate in vitro into cardiomyocytes, we provide for the first time evidence that cardiac TCSC residing in bone marrow but not “plastic” HSC may account for cardiac differentiation of BM-derived cells. These observations provide rationale for further studies aimed at optimizing therapeutic cardiac regeneration by BM-derived non-hematopoietic cardiac TCSC. Finally, our observation that the number of marrow derived mobile/circulating cardiac TCSC is the highest in BM of young animals and decreases with age provides a novel insight into aging and may explain why the heart regeneration process becomes less effective in older individuals.

scholarly journals One-Year Safety Analysis of the COMPARE-AMI Trial: Comparison of Intracoronary Injection of CD133+ Bone Marrow Stem Cells to Placebo in Patients after Acute Myocardial Infarction and Left Ventricular Dysfunction

2011 ◽  
Vol 2011 ◽  
pp. 1-6 ◽  
Author(s):  
Samer Mansour ◽  
Denis-Claude Roy ◽  
Vincent Bouchard ◽  
Louis Mathieu Stevens ◽  
Francois Gobeil ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Acute Myocardial Infarction ◽  
Stem Cells ◽  
Bone Marrow ◽  
Left Ventricular Dysfunction ◽  
Ventricular Dysfunction ◽  
Safety Analysis ◽  
Left Ventricular ◽  
Intracoronary Injection ◽  
One Year

Bone marrow stem cell therapy has emerged as a promising approach to improve healing of the infarcted myocardium. Despite initial excitement, recent clinical trials using non-homogenous stem cells preparations showed variable and mixed results. Selected CD133+ hematopoietic stem cells are candidate cells with high potential. Herein, we report the one-year safety analysis on the initial 20 patients enrolled in the COMPARE-AMI trial, the first double-blind randomized controlled trial comparing the safety, efficacy, and functional effect of intracoronary injection of selected CD133+ cells to placebo following acute myocardial infarction with persistent left ventricular dysfunction. At one year, there is no protocol-related complication to report such as death, myocardial infarction, stroke, or sustained ventricular arrhythmia. In addition, the left ventricular ejection fraction significantly improved at four months as compared to baseline and remained significantly higher at one year. These data indicate that in the setting of the COMPARE-AMI trial, the intracoronary injection of selected CD133+ stem cells is secure and feasible in patients with left ventricle dysfunction following acute myocardial infarction.

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