A Phase II study of autologous mesenchymal stromal cells and c-kit positive cardiac cells, alone or in combination, in patients with ischaemic heart failure: the CCTRN CONCERT-HF trial

doi:10.1002/ejhf.2178

A Phase II study of autologous mesenchymal stromal cells and c-kit positive cardiac cells, alone or in combination, in patients with ischaemic heart failure: the CCTRN CONCERT-HF trial

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Abstract

Aims: CONCERT-HF is an NHLBI-sponsored, double-blind, placebo-controlled, Phase II trial designed to determine whether treatment with autologous bone marrow-derived mesenchymal stromal cells (MSCs) and c-kit positive cardiac cells (CPCs), given alone or in combination, is feasible, safe, and beneficial in patients with heart failure (HF) caused by ischaemic cardiomyopathy. Methods and results: Patients were randomized (1:1:1:1) to transendocardial injection of MSCs combined with CPCs, MSCs alone, CPCs alone, or placebo, and followed for 12 months. Seven centres enrolled 125 participants with left ventricular ejection fraction of 28.6 ± 6.1% and scar size 19.4 ± 5.8%, in New York Heart Association class II or III. The proportion of major adverse cardiac events (MACE) was significantly decreased by CPCs alone (−22% vs. placebo, P = 0.043). Quality of life (Minnesota Living with Heart Failure Questionnaire score) was significantly improved by MSCs alone (P = 0.050) and MSCs + CPCs (P = 0.023) vs. placebo. Left ventricular ejection fraction, left ventricular volumes, scar size, 6-min walking distance, and peak oxygen consumption did not differ significantly among groups. Conclusions: This is the first multicentre trial assessing CPCs and a combination of two cell types from different tissues in HF patients. The results show that treatment is safe and feasible. Even with maximal guideline-directed therapy, both CPCs and MSCs were associated with improved clinical outcomes (MACE and quality of life, respectively) in ischaemic HF without affecting left ventricular function or structure, suggesting possible systemic or paracrine cellular mechanisms. Combining MSCs with CPCs was associated with improvement in both these outcomes. These results suggest potential important beneficial effects of CPCs and MSCs and support further investigation in HF patients.

Original language	English
Pages (from-to)	661-674
Number of pages	14
Journal	European Journal of Heart Failure
Volume	23
Issue number	4
DOIs	https://doi.org/10.1002/ejhf.2178
State	Published - Apr 2021

Bibliographical note

Funding Information:
: All investigators received funding from the NIH National Heart, Lung, and Blood Institute (NHLBI) for conduct of the CONCERT‐HF trial through the Cardiovascular Cell Therapy Research Network (CCTRN). R.F.E. is a staff member of the National Heart, Lung, and Blood Institute (NHLBI), the source of funding for the CONCERT‐HF trial. The views expressed in this article are those of the authors and do not necessarily represent the views of the NHLBI, National Institutes of Health, or the United States Department of Health and Human Services. I.H.S. is currently a staff member of the National Institute of Diabetes and Digestive, and Kidney Diseases (NIDDK). The views expressed in this article are those of the authors and do not necessarily represent the views of the NIDDK, National Institutes of Health, or the United States Department of Health and Human Services. J.M.H. is a scientific co‐founder and holds equity in Vestion, Inc. Vestion did not fund or participate in this study. Dr. Hare's role in Vestion has been disclosed to the University of Miami and to the steering committee of the CCTRN, and appropriate management plans have been instituted. T.D.H. has served as a consultant for Biosense Webster. C.J.P. has served as a consultant for XyloCor, Caladrius, Imbria, and Biocardia; and has grants with Adelphi Values, Brigham and Women's Hospital, Department of Defense, Gilead Sciences, Inc., McJunkin Foundation, Mesoblast, and Sanofi US. E.C.P. has served as a consultant for Mesoblast. D.A.T. is co‐founder of Stem Cell Security. P.C.Y. has served as a consultant for Terumo. All other authors have nothing to disclose. Conflict of interest

Funding Information:
This work was supported by National Institutes of Health [HL087318, HL113530, HL113460, HL087394, HL113457, HL087366, HL087365].

Publisher Copyright:
© 2021 European Society of Cardiology.

Keywords

Cell-based therapy
Clinical trial
Heart failure

ASJC Scopus subject areas

Cardiology and Cardiovascular Medicine

Access to Document

10.1002/ejhf.2178

Cite this

@article{53c2072b4b994d7ca5683d64ba038d6f,

title = "A Phase II study of autologous mesenchymal stromal cells and c-kit positive cardiac cells, alone or in combination, in patients with ischaemic heart failure: the CCTRN CONCERT-HF trial",

abstract = "Aims: CONCERT-HF is an NHLBI-sponsored, double-blind, placebo-controlled, Phase II trial designed to determine whether treatment with autologous bone marrow-derived mesenchymal stromal cells (MSCs) and c-kit positive cardiac cells (CPCs), given alone or in combination, is feasible, safe, and beneficial in patients with heart failure (HF) caused by ischaemic cardiomyopathy. Methods and results: Patients were randomized (1:1:1:1) to transendocardial injection of MSCs combined with CPCs, MSCs alone, CPCs alone, or placebo, and followed for 12 months. Seven centres enrolled 125 participants with left ventricular ejection fraction of 28.6 ± 6.1% and scar size 19.4 ± 5.8%, in New York Heart Association class II or III. The proportion of major adverse cardiac events (MACE) was significantly decreased by CPCs alone (−22% vs. placebo, P = 0.043). Quality of life (Minnesota Living with Heart Failure Questionnaire score) was significantly improved by MSCs alone (P = 0.050) and MSCs + CPCs (P = 0.023) vs. placebo. Left ventricular ejection fraction, left ventricular volumes, scar size, 6-min walking distance, and peak oxygen consumption did not differ significantly among groups. Conclusions: This is the first multicentre trial assessing CPCs and a combination of two cell types from different tissues in HF patients. The results show that treatment is safe and feasible. Even with maximal guideline-directed therapy, both CPCs and MSCs were associated with improved clinical outcomes (MACE and quality of life, respectively) in ischaemic HF without affecting left ventricular function or structure, suggesting possible systemic or paracrine cellular mechanisms. Combining MSCs with CPCs was associated with improvement in both these outcomes. These results suggest potential important beneficial effects of CPCs and MSCs and support further investigation in HF patients.",

keywords = "Cell-based therapy, Clinical trial, Heart failure",

author = "Roberto Bolli and Mitrani, {Raul D.} and Hare, {Joshua M.} and Pepine, {Carl J.} and Perin, {Emerson C.} and Willerson, {James T.} and Traverse, {Jay H.} and Henry, {Timothy D.} and Yang, {Phillip C.} and Murphy, {Michael P.} and March, {Keith L.} and Schulman, {Ivonne H.} and Sohail Ikram and Lee, {David P.} and Connor O'Brien and Lima, {Joao A.} and Ostovaneh, {Mohammad R.} and Bharath Ambale-Venkatesh and Gregory Lewis and Aisha Khan and Ketty Bacallao and Krystalenia Valasaki and Bangon Longsomboon and Gee, {Adrian P.} and Sara Richman and Taylor, {Doris A.} and Dejian Lai and Sayre, {Shelly L.} and Judy Bettencourt and Vojvodic, {Rachel W.} and Cohen, {Michelle L.} and Lara Simpson and David Aguilar and Catalin Loghin and Lem Moy{\'e} and Ebert, {Ray F.} and Davis, {Barry R.} and Simari, {Robert D.}",

note = "Funding Information: : All investigators received funding from the NIH National Heart, Lung, and Blood Institute (NHLBI) for conduct of the CONCERT‐HF trial through the Cardiovascular Cell Therapy Research Network (CCTRN). R.F.E. is a staff member of the National Heart, Lung, and Blood Institute (NHLBI), the source of funding for the CONCERT‐HF trial. The views expressed in this article are those of the authors and do not necessarily represent the views of the NHLBI, National Institutes of Health, or the United States Department of Health and Human Services. I.H.S. is currently a staff member of the National Institute of Diabetes and Digestive, and Kidney Diseases (NIDDK). The views expressed in this article are those of the authors and do not necessarily represent the views of the NIDDK, National Institutes of Health, or the United States Department of Health and Human Services. J.M.H. is a scientific co‐founder and holds equity in Vestion, Inc. Vestion did not fund or participate in this study. Dr. Hare's role in Vestion has been disclosed to the University of Miami and to the steering committee of the CCTRN, and appropriate management plans have been instituted. T.D.H. has served as a consultant for Biosense Webster. C.J.P. has served as a consultant for XyloCor, Caladrius, Imbria, and Biocardia; and has grants with Adelphi Values, Brigham and Women's Hospital, Department of Defense, Gilead Sciences, Inc., McJunkin Foundation, Mesoblast, and Sanofi US. E.C.P. has served as a consultant for Mesoblast. D.A.T. is co‐founder of Stem Cell Security. P.C.Y. has served as a consultant for Terumo. All other authors have nothing to disclose. Conflict of interest Funding Information: This work was supported by National Institutes of Health [HL087318, HL113530, HL113460, HL087394, HL113457, HL087366, HL087365]. Publisher Copyright: {\textcopyright} 2021 European Society of Cardiology.",

year = "2021",

month = apr,

doi = "10.1002/ejhf.2178",

language = "English",

volume = "23",

pages = "661--674",

number = "4",

}

TY - JOUR

T1 - A Phase II study of autologous mesenchymal stromal cells and c-kit positive cardiac cells, alone or in combination, in patients with ischaemic heart failure

T2 - the CCTRN CONCERT-HF trial

AU - Bolli, Roberto

AU - Mitrani, Raul D.

AU - Hare, Joshua M.

AU - Pepine, Carl J.

AU - Perin, Emerson C.

AU - Willerson, James T.

AU - Traverse, Jay H.

AU - Henry, Timothy D.

AU - Yang, Phillip C.

AU - Murphy, Michael P.

AU - March, Keith L.

AU - Schulman, Ivonne H.

AU - Ikram, Sohail

AU - Lee, David P.

AU - O'Brien, Connor

AU - Lima, Joao A.

AU - Ostovaneh, Mohammad R.

AU - Ambale-Venkatesh, Bharath

AU - Lewis, Gregory

AU - Khan, Aisha

AU - Bacallao, Ketty

AU - Valasaki, Krystalenia

AU - Longsomboon, Bangon

AU - Gee, Adrian P.

AU - Richman, Sara

AU - Taylor, Doris A.

AU - Lai, Dejian

AU - Sayre, Shelly L.

AU - Bettencourt, Judy

AU - Vojvodic, Rachel W.

AU - Cohen, Michelle L.

AU - Simpson, Lara

AU - Aguilar, David

AU - Loghin, Catalin

AU - Moyé, Lem

AU - Ebert, Ray F.

AU - Davis, Barry R.

AU - Simari, Robert D.

N1 - Funding Information: : All investigators received funding from the NIH National Heart, Lung, and Blood Institute (NHLBI) for conduct of the CONCERT‐HF trial through the Cardiovascular Cell Therapy Research Network (CCTRN). R.F.E. is a staff member of the National Heart, Lung, and Blood Institute (NHLBI), the source of funding for the CONCERT‐HF trial. The views expressed in this article are those of the authors and do not necessarily represent the views of the NHLBI, National Institutes of Health, or the United States Department of Health and Human Services. I.H.S. is currently a staff member of the National Institute of Diabetes and Digestive, and Kidney Diseases (NIDDK). The views expressed in this article are those of the authors and do not necessarily represent the views of the NIDDK, National Institutes of Health, or the United States Department of Health and Human Services. J.M.H. is a scientific co‐founder and holds equity in Vestion, Inc. Vestion did not fund or participate in this study. Dr. Hare's role in Vestion has been disclosed to the University of Miami and to the steering committee of the CCTRN, and appropriate management plans have been instituted. T.D.H. has served as a consultant for Biosense Webster. C.J.P. has served as a consultant for XyloCor, Caladrius, Imbria, and Biocardia; and has grants with Adelphi Values, Brigham and Women's Hospital, Department of Defense, Gilead Sciences, Inc., McJunkin Foundation, Mesoblast, and Sanofi US. E.C.P. has served as a consultant for Mesoblast. D.A.T. is co‐founder of Stem Cell Security. P.C.Y. has served as a consultant for Terumo. All other authors have nothing to disclose. Conflict of interest Funding Information: This work was supported by National Institutes of Health [HL087318, HL113530, HL113460, HL087394, HL113457, HL087366, HL087365]. Publisher Copyright: © 2021 European Society of Cardiology.

PY - 2021/4

Y1 - 2021/4

N2 - Aims: CONCERT-HF is an NHLBI-sponsored, double-blind, placebo-controlled, Phase II trial designed to determine whether treatment with autologous bone marrow-derived mesenchymal stromal cells (MSCs) and c-kit positive cardiac cells (CPCs), given alone or in combination, is feasible, safe, and beneficial in patients with heart failure (HF) caused by ischaemic cardiomyopathy. Methods and results: Patients were randomized (1:1:1:1) to transendocardial injection of MSCs combined with CPCs, MSCs alone, CPCs alone, or placebo, and followed for 12 months. Seven centres enrolled 125 participants with left ventricular ejection fraction of 28.6 ± 6.1% and scar size 19.4 ± 5.8%, in New York Heart Association class II or III. The proportion of major adverse cardiac events (MACE) was significantly decreased by CPCs alone (−22% vs. placebo, P = 0.043). Quality of life (Minnesota Living with Heart Failure Questionnaire score) was significantly improved by MSCs alone (P = 0.050) and MSCs + CPCs (P = 0.023) vs. placebo. Left ventricular ejection fraction, left ventricular volumes, scar size, 6-min walking distance, and peak oxygen consumption did not differ significantly among groups. Conclusions: This is the first multicentre trial assessing CPCs and a combination of two cell types from different tissues in HF patients. The results show that treatment is safe and feasible. Even with maximal guideline-directed therapy, both CPCs and MSCs were associated with improved clinical outcomes (MACE and quality of life, respectively) in ischaemic HF without affecting left ventricular function or structure, suggesting possible systemic or paracrine cellular mechanisms. Combining MSCs with CPCs was associated with improvement in both these outcomes. These results suggest potential important beneficial effects of CPCs and MSCs and support further investigation in HF patients.

AB - Aims: CONCERT-HF is an NHLBI-sponsored, double-blind, placebo-controlled, Phase II trial designed to determine whether treatment with autologous bone marrow-derived mesenchymal stromal cells (MSCs) and c-kit positive cardiac cells (CPCs), given alone or in combination, is feasible, safe, and beneficial in patients with heart failure (HF) caused by ischaemic cardiomyopathy. Methods and results: Patients were randomized (1:1:1:1) to transendocardial injection of MSCs combined with CPCs, MSCs alone, CPCs alone, or placebo, and followed for 12 months. Seven centres enrolled 125 participants with left ventricular ejection fraction of 28.6 ± 6.1% and scar size 19.4 ± 5.8%, in New York Heart Association class II or III. The proportion of major adverse cardiac events (MACE) was significantly decreased by CPCs alone (−22% vs. placebo, P = 0.043). Quality of life (Minnesota Living with Heart Failure Questionnaire score) was significantly improved by MSCs alone (P = 0.050) and MSCs + CPCs (P = 0.023) vs. placebo. Left ventricular ejection fraction, left ventricular volumes, scar size, 6-min walking distance, and peak oxygen consumption did not differ significantly among groups. Conclusions: This is the first multicentre trial assessing CPCs and a combination of two cell types from different tissues in HF patients. The results show that treatment is safe and feasible. Even with maximal guideline-directed therapy, both CPCs and MSCs were associated with improved clinical outcomes (MACE and quality of life, respectively) in ischaemic HF without affecting left ventricular function or structure, suggesting possible systemic or paracrine cellular mechanisms. Combining MSCs with CPCs was associated with improvement in both these outcomes. These results suggest potential important beneficial effects of CPCs and MSCs and support further investigation in HF patients.

KW - Cell-based therapy

KW - Clinical trial

KW - Heart failure

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U2 - 10.1002/ejhf.2178

DO - 10.1002/ejhf.2178

M3 - Article

C2 - 33811444

AN - SCOPUS:85104333248

SN - 1388-9842

VL - 23

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EP - 674

JO - European Journal of Heart Failure

JF - European Journal of Heart Failure

IS - 4

ER -

A Phase II study of autologous mesenchymal stromal cells and c-kit positive cardiac cells, alone or in combination, in patients with ischaemic heart failure: the CCTRN CONCERT-HF trial

Abstract

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Keywords

ASJC Scopus subject areas

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