Identification of cardiovascular risk factors associated with bone marrow cell subsets in patients with STEMI: a biorepository evaluation from the CCTRN TIME and LateTIME clinical trials

Contreras, Ariadna; Orozco, Aaron; Resende, Micheline; Schutt, Robert C.; Traverse, Jay H.; Henry, Timothy D.; Lai, Dejian; Cooke, John P.; Bolli, Roberto; Cohen, Mark H.; Moyé, Lemuel A.; Pepine, Carl J.; Yang, Phillip C.; Perin, Emerson C.; Willerson, James T.; Taylor, Doris A.

doi:10.1007/s00395-016-0592-z

Cited by 17 publications

(6 citation statements)

References 59 publications

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“…This mechanism was shown already 12 years ago to be associated with progression in atherosclerosis and coronary artery disease ( Werner et al, 2005 ). Recently, the investigation of responders to cardiac repair in the CCTRN-trials obtained similar findings in bone marrow of BMDC treated non-responsive chronic ischemic heart failure patients ( Bhatnagar et al, 2016 , Contreras et al, 2017 ). In the PERFECT trial we found a striking difference in cardiac recovery between responders and non-responders.…”

Section: Discussionmentioning

confidence: 68%

“…Yet, in these trials, clinically relevant improvements of LVEF as well as non-responsive patients were observed both in treatment and placebo groups ( Henry et al, 2016 , Nasseri et al, 2014 , Bartunek et al, 2016 ). This has raised the question of induction of reparative mechanisms independent of stem cell application and potential suppressive factors of vascular repair associated with CD34 + Endothelial Progenitor Cells (EPC) ( Werner et al, 2005 , Taylor et al, 2016 , Bhatnagar et al, 2016 , Contreras et al, 2017 ).…”

Section: Introductionmentioning

confidence: 99%

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Cardiac Function Improvement and Bone Marrow Response –

Steinhoff¹,

Nesteruk²,

Wolfien

et al. 2017

EBioMedicine

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ObjectiveThe phase III clinical trial PERFECT was designed to assess clinical safety and efficacy of intramyocardial CD133+ bone marrow stem cell treatment combined with CABG for induction of cardiac repair.DesignMulticentre, double-blinded, randomised placebo controlled trial.SettingThe study was conducted across six centres in Germany October 2009 through March 2016 and stopped due slow recruitment after positive interim analysis in March 2015.ParticipantsPost-infarction patients with chronic ischemia and reduced LVEF (25–50%). Interventions: Eighty-two patients were randomised to two groups receiving intramyocardial application of 5 ml placebo or a suspension of 0.5–5 × 106 CD133+.OutcomePrimary endpoint was delta (∆) LVEF at 180 days (d) compared to baseline measured in MRI.Findings (prespecified)Safety (n = 77): 180 d survival was 100%, MACE n = 2, SAE n = 49, without difference between placebo and CD133+. Efficacy (n = 58): The LVEF improved from baseline LVEF 33.5% by + 9.6% at 180 d, p = 0.001 (n = 58). Treatment groups were not different in ∆ LVEF (ANCOVA: Placebo + 8.8% vs. CD133+ + 10.4%, ∆ CD133+ vs placebo + 2.6%, p = 0.4).Findings (post hoc)Responders (R) classified by ∆ LVEF ≥ 5% after 180 d were 60% of the patients (35/58) in both treatment groups. ∆ LVEF in ANCOVA was + 17.1% in (R) vs. non-responders (NR) (∆ LVEF 0%, n = 23). NR were characterized by a preoperative response signature in peripheral blood with reduced CD133+ EPC (RvsNR: p = 0.005) and thrombocytes (p = 0.004) in contrast to increased Erythropoeitin (p = 0.02), and SH2B3 mRNA expression (p = 0.073). Actuarial computed mean survival time was 76.9 ± 3.32 months (R) vs. + 72.3 ± 5.0 months (NR), HR 0.3 [Cl 0.07–1.2]; p = 0.067.Using a machine learning 20 biomarker response parameters were identified allowing preoperative discrimination with an accuracy of 80% (R) and 84% (NR) after 10-fold cross-validation.InterpretationThe PERFECT trial analysis demonstrates that the regulation of induced cardiac repair is linked to the circulating pool of CD133 + EPC and thrombocytes, associated with SH2B3 gene expression. Based on these findings, responders to cardiac functional improvement may be identified by a peripheral blood biomarker signature.TRIAL REGISTRATION: ClinicalTrials.govNCT00950274.

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Section: Discussionmentioning

confidence: 68%

Section: Introductionmentioning

confidence: 99%

Cardiac Function Improvement and Bone Marrow Response –

Steinhoff¹,

Nesteruk²,

Wolfien

et al. 2017

EBioMedicine

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“…In particular, Gap19 inhibits HC currents by perturbing CT interaction with a cytoplasmic loop (CL)-located binding site, which is necessary for Cx43 HC opening (reviewed in [ 13 ]). Making use of Gap19, we demonstrated protection against cardiac ischemia/reperfusion injury and cardiomyocyte cell death [ 6 , 14 ]. Gap19 is increasingly used to probe for Cx43 HC involvement in various cardiac, brain, and other disease models [ 7 , 8 , 15 , 16 , 17 , 18 ], making a more detailed analysis indicated and timely.…”

Section: Introductionmentioning

confidence: 99%

Gap19, a Cx43 Hemichannel Inhibitor, Acts as a Gating Modifier That Decreases Main State Opening While Increasing Substate Gating

Lissoni

Wang

Nezlobinskii

et al. 2020

IJMS

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Cx43 hemichannels (HCs) are electrically and chemically gated transmembrane pores with low open probability and multiple conductance states, which makes kinetic studies of channel gating in large datasets challenging. Here, we developed open access software, named HemiGUI, to analyze HC gating transitions and investigated voltage-induced HC opening based on up to ≈4000 events recorded in HeLa-Cx43-overexpressing cells. We performed a detailed characterization of Cx43 HC gating profiles and specifically focused on the role of the C-terminal tail (CT) domain by recording the impact of adding an EGFP tag to the Cx43 CT end (Cx43-EGFP) or by supplying the Cx43 HC-inhibiting peptide Gap19 that interferes with CT interaction with the cytoplasmic loop (CL). We found that Gap19 not only decreased HC opening activity to the open state (≈217 pS) but also increased the propensity of subconductance (≈80 pS) transitions that additionally became slower as compared to the control. The work demonstrates that large sample transition analysis allows detailed investigations on Cx43 HC gating and shows that Gap19 acts as a HC gating modifier by interacting with the CT that forms a crucial gating element.

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“…In contrast, Ly6C lo M2 macrophages express and release anti-inflammatory cytokines such as VEGF and TGF-β, contributing to CF activation, angiogenesis and wound healing 76 . In addition, infusion of IL-10 in vivo significantly increased the expression of M2 marker genes along with CF activation (as evidenced by CF proliferation, recruitment and ECM accumulation), and ultimately led to the improvement of cardiac remodeling both structurally and functionally 77 . A recent study using flow cytometry and RNA sequencing technology successfully mapped the transcriptomes of polarized macrophage during the first week post MI 78 : within the first day post MI, macrophages showed the unique features of pro-inflammatory proprieties and ECM degradation, while the macrophages on day 3 displayed the upregulation of proliferation and phagocytosis as well as the reprogramming of metabolism; macrophages on days 7 exhibited proreparative signatures characterized by the elevation of Col1a1, Col3a1, and postn expression.…”

Section: Immune Cellsmentioning

confidence: 99%

The Roles of Noncardiomyocytes in Cardiac Remodeling

Yang

Liu

et al. 2020

Int. J. Biol. Sci.

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Cardiac remodeling is a common characteristic of almost all forms of heart disease, including cardiac infarction, valvular diseases, hypertension, arrhythmia, dilated cardiomyopathy and other conditions. It is not merely a simple outcome induced by an increase in the workload of cardiomyocytes (CMs). The remodeling process is accompanied by abnormalities of cardiac structure as well as disturbance of cardiac function, and emerging evidence suggests that a wide range of cells in the heart participate in the initiation and development of cardiac remodeling. Other than CMs, there are numerous noncardiomyocytes (non-CMs) that regulate the process of cardiac remodeling, such as cardiac fibroblasts and immune cells (including macrophages, lymphocytes, neutrophils, and mast cells). In this review, we summarize recent knowledge regarding the definition and significant effects of various non-CMs in the pathogenesis of cardiac remodeling, with a particular emphasis on the involved signaling mechanisms. In addition, we discuss the properties of non-CMs, which serve as targets of many cardiovascular drugs that reduce adverse cardiac remodeling.

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Identification of cardiovascular risk factors associated with bone marrow cell subsets in patients with STEMI: a biorepository evaluation from the CCTRN TIME and LateTIME clinical trials

Cited by 17 publications

References 59 publications

Cardiac Function Improvement and Bone Marrow Response –

Cardiac Function Improvement and Bone Marrow Response –

Gap19, a Cx43 Hemichannel Inhibitor, Acts as a Gating Modifier That Decreases Main State Opening While Increasing Substate Gating

The Roles of Noncardiomyocytes in Cardiac Remodeling

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