Ventricular remodeling in ischemic heart failure stratifies responders to stem cell therapy

Yamada, Satsuki; Arrell, D. Kent; Rosenow, Christian; Bartúnek, Jozef; Behfar, Atta; Terzic, André

doi:10.1002/sctm.19-0149

Cited by 17 publications

(16 citation statements)

References 25 publications

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“…The experience obtained herein is consistent with the recent validation of baseline LV enlargement as a modifier of therapeutic response in experimental cell therapy. 21 These findings are in line with known relationship between LV volumes and outcomes in heart failure and therapeutic response to traditional medical and device-based interventions in heart failure [22][23][24] with therapeutic effect being absent once heart failure progressed beyond the point of potentially meaningful clinical impact. Notwithstanding, the experience obtained herein should be considered as hypothesis generating with need for independent validation in prospectively designed trials incorporating target patient selection using the LV volume range as heart failure severity criterion.…”

Section: Discussionsupporting

confidence: 71%

Cardiopoietic stem cell therapy in ischaemic heart failure: long‐term clinical outcomes

et al. 2020

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Aims This study aims to explore long-term clinical outcomes of cardiopoiesis-guided stem cell therapy for ischaemic heart failure assessed in the Congestive Heart Failure Cardiopoietic Regenerative Therapy (CHART-1) trial. Methods and results CHART-1 is a multinational, randomized, and double-blind trial conducted in 39 centres in heart failure patients (n = 315) on standard-of-care therapy. The 'active' group received cardiopoietic stem cells delivered intramyocardially using a retention-enhanced catheter. The 'control' group underwent patient-level sham procedure. Patients were followed up to 104 weeks. In the entire study population, results of the primary hierarchical composite outcome were maintained neutral at Week 52 [Mann-Whitney estimator 0.52, 95% confidence interval (CI) 0.45-0.59, P = 0.51]. Landmark analyses suggested late clinical benefit in patients with significant left ventricular enlargement receiving adequate dosing. Specifically, beyond 100 days of follow-up, patients with left ventricular end-diastolic volume of 200-370 mL treated with ≤19 injections of cardiopoietic stem cells showed reduced risk of death or cardiovascular hospitalization (hazard ratio 0.38, 95% CI 0.16-0.91, P = 0.031) and cardiovascular death or heart failure hospitalization (hazard ratio 0.28, 95% CI 0.09-0.94, P = 0.040). Cardiopoietic stem cell therapy was well tolerated long term with no difference in safety readouts compared with sham at 2 years. Conclusions Longitudinal follow-up documents that cardiopoietic stem cell therapy is overall safe, and post hoc analyses suggest benefit in an ischaemic heart failure subpopulation defined by advanced left ventricular enlargement on tolerable stem cell dosing. The long-term clinical follow-up thus offers guidance for future targeted trials.

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Section: Discussionsupporting

confidence: 71%

Cardiopoietic stem cell therapy in ischaemic heart failure: long‐term clinical outcomes

et al. 2020

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“…19,20 While genetic and structural determinants intrinsic to recipient hearts are recognized, less is known regarding stem cell characteristics governing therapeutic effectiveness. 16,21,22 We explored here, at systems level, cardiopoietic cell imprints that segregate with benefit. Merging multiomics datasets provides inclusive, unbiased strategies enabling functional prioritization of complex multidimensional outputs.…”

Section: Discussionmentioning

confidence: 99%

“…In fact, it presented as the most extensively enriched (miR-146, P = 9.27 Â 10 À10 ) of predicted upstream miRNA regulators and had the greatest extent of observed downregulated change (miR-146b-5p, 2.84-fold, P = 5.97 Â 10 À3 ) among cohorts and repeated measures ANOVA. Proteome was extracted from disease severity titrated infarcted hearts, 16 and analyzed by label-free peptide quantification following nano-flow liquid chromatography electrospray tandem mass spectrometry. 17 Protein identities were assigned and quantified using MaxQuant v.1.5.1.2, and differential expression calculated by two-sided ANOVA with Gaussian linked function using R. 17 Cohort level differences were evaluated in IPA, using Fisher's exact test with B-H FDR correction to identify enriched cardiac adverse effects and prioritized cardiovascular system development functions.…”

Section: Infarcted Heart Assessmentmentioning

confidence: 99%

Secretome Signature of Cardiopoietic Cells Echoed in Rescued infarcted Heart Proteome

Arrell

Crespo‐Diaz

Yamada

et al. 2021

Stem Cells Translational Medicine

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Stem cell paracrine activity is implicated in cardiac repair. Linkage between secretome functionality and therapeutic outcome was here interrogated by systems analytics of biobanked human cardiopoietic cells, a regenerative biologic in advanced clinical trials. Protein chip array identified 155 proteins differentially secreted by cardiopoietic cells with clinical benefit, expanded into a 520 node network, collectively revealing inherent vasculogenic properties along with cardiac and smooth muscle differentiation and development. Next generation RNA sequencing, refined by pathway analysis, pinpointed miR-146 dependent regulation upstream of the decoded secretome. Intracellular and extracellular integration unmasked commonality across cardiovasculogenic processes. Mirroring the secretome pattern, infarcted hearts benefiting from cardiopoietic cell therapy restored the disease proteome engaging cardiovascular system functions. The cardiopoietic cell secretome thus confers a therapeutic molecular imprint on recipient hearts, with response informed by predictive systems profiling.

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“…Eight‐ to 12‐week‐old athymic nude male mice (n = 14) underwent myocardial infarction surgery imposed by permanent ligation of the left anterior descending artery, followed by 1:1 randomization in the cell (n = 7) or vehicle control (n = 7) treatment groups. Stem cells were transfected with Brachyury, incubated for 72 hours (>90% viability) and epicardially delivered into six sites of the infarcted left ventricular (LV) wall (600 000 cells per heart in 15 μL Hanks' Balanced Salt Solution [HBSS; Thermo Fisher, 14025092]) 36 . Stem cell‐free vehicle treatment, using the same delivery protocol, consisted of delivering HBSS (15 μL per heart) injected into the LV.…”

Section: Methodsmentioning

confidence: 99%

Brachyury engineers cardiac repair competent stem cells

Yamada

Shi

et al. 2020

Stem Cells Translational Medicine

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To optimize the regenerative proficiency of stem cells, a cardiopoietic protein-based cocktail consisting of multiple growth factors has been developed and advanced into clinical trials for treatment of ischemic heart failure. Streamlining the inductors of cardiopoiesis would address the resource intensive nature of the current stem cell enhancement protocol. To this end, the microencapsulated-modified-mRNA (M 3 RNA) technique was here applied to introduce early cardiogenic genes into human adipose-derived mesenchymal stem cells (AMSCs). A single mesodermal transcription factor, Brachyury, was sufficient to trigger high expression of cardiopoietic markers, Nkx2.5 and Mef2c. Engineered cardiopoietic stem cells (eCP) featured a transcriptome profile distinct from pre-engineered AMSCs. In vitro, eCP demonstrated protective antioxidant capacity with enhanced superoxide dismutase expression and activity; a vasculogenic secretome driving angiogenic tube formation; and macrophage polarizing immunomodulatory properties. In vivo, in a murine model of myocardial infarction, intramyocardial delivery of eCP (600 000 cells per heart) improved cardiac performance and protected against decompensated heart failure. Thus, heart repair competent stem cells, armed with antioxidant, vasculogenic, and immunomodulatory traits, are here engineered through a protein-independent single gene manipulation, expanding the available regenerative toolkit.

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Ventricular remodeling in ischemic heart failure stratifies responders to stem cell therapy

Cited by 17 publications

References 25 publications

Cardiopoietic stem cell therapy in ischaemic heart failure: long‐term clinical outcomes

Cardiopoietic stem cell therapy in ischaemic heart failure: long‐term clinical outcomes

Secretome Signature of Cardiopoietic Cells Echoed in Rescued infarcted Heart Proteome

Brachyury engineers cardiac repair competent stem cells

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