Autologous mesenchymal stem cells produce concordant improvements in regional function, tissue perfusion, and fibrotic burden when administered to patients undergoing coronary artery bypass grafting

The prospective randomized study of mesenchymal stem cell therapy in patients undergoing cardiac surgery (PROMETHEUS) trial

Vasileios Karantalis, Darcy L. Difede, Gary Gerstenblith, Si Pham, James Symes, Juan Pablo Zambrano, Joel Fishman, Pradip Pattany, Ian McNiece, John Conte, Steven Schulman, Katherine Wu, Ashish Shah, Elayne Breton, Janice Davis-Sproul, Richard Schwarz, Gary Feigenbaum, Muzammil Mushtaq, Viky Y. Suncion, Albert C. Lardo & 7 others Ivan Borrello, Adam Mendizabal, Tomer Z. Karas, John Byrnes, Maureen Lowery, Alan W. Heldman, Joshua M. Hare

Research output: Contribution to journalArticle

166 Citations (Scopus)

Abstract

Rationale: Although accumulating data support the efficacy of intramyocardial cell-based therapy to improve left ventricular (LV) function in patients with chronic ischemic cardiomyopathy undergoing CABG, the underlying mechanism and impact of cell injection site remain controversial. Mesenchymal stem cells (MSCs) improve LV structure and function through several effects including reducing fibrosis, neoangiogenesis, and neomyogenesis. Objective: To test the hypothesis that the impact on cardiac structure and function after intramyocardial injections of autologous MSCs results from a concordance of prorecovery phenotypic effects. Methods and results: Six patients were injected with autologous MSCs into akinetic/hypokinetic myocardial territories not receiving bypass graft for clinical reasons. MRI was used to measure scar, perfusion, wall thickness, and contractility at baseline, at 3, 6, and 18 months and to compare structural and functional recovery in regions that received MSC injections alone, revascularization alone, or neither. A composite score of MRI variables was used to assess concordance of antifibrotic effects, perfusion, and contraction at different regions. After 18 months, subjects receiving MSCs exhibited increased LV ejection fraction (+9.4±1.7%, P=0.0002) and decreased scar mass (-47.5±8.1%; P<0.0001) compared with baseline. MSC-injected segments had concordant reduction in scar size, perfusion, and contractile improvement (concordant score: 2.93±0.07), whereas revascularized (0.5±0.21) and nontreated segments (-0.07±0.34) demonstrated nonconcordant changes (P<0.0001 versus injected segments). Conclusions: Intramyocardial injection of autologous MSCs into akinetic yet nonrevascularized segments produces comprehensive regional functional restitution, which in turn drives improvement in global LV function. These findings, although inconclusive because of lack of placebo group, have important therapeutic and mechanistic hypothesis-generating implications. Clinical trial registration: URL: http://clinicaltrials.gov/show/NCT00587990. Unique identifier: NCT00587990.

Original languageEnglish (US)
Pages (from-to)1302-1310
Number of pages9
JournalCirculation research
Volume114
Issue number8
DOIs
StatePublished - Jan 1 2014

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Cell- and Tissue-Based Therapy
Mesenchymal Stromal Cells
Coronary Artery Bypass
Thoracic Surgery
Perfusion
Prospective Studies
Left Ventricular Function
Cicatrix
Injections
Cardiomyopathies
Stroke Volume
Fibrosis
Placebos
Clinical Trials
Transplants

All Science Journal Classification (ASJC) codes

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Karantalis, Vasileios ; Difede, Darcy L. ; Gerstenblith, Gary ; Pham, Si ; Symes, James ; Zambrano, Juan Pablo ; Fishman, Joel ; Pattany, Pradip ; McNiece, Ian ; Conte, John ; Schulman, Steven ; Wu, Katherine ; Shah, Ashish ; Breton, Elayne ; Davis-Sproul, Janice ; Schwarz, Richard ; Feigenbaum, Gary ; Mushtaq, Muzammil ; Suncion, Viky Y. ; Lardo, Albert C. ; Borrello, Ivan ; Mendizabal, Adam ; Karas, Tomer Z. ; Byrnes, John ; Lowery, Maureen ; Heldman, Alan W. ; Hare, Joshua M. / Autologous mesenchymal stem cells produce concordant improvements in regional function, tissue perfusion, and fibrotic burden when administered to patients undergoing coronary artery bypass grafting : The prospective randomized study of mesenchymal stem cell therapy in patients undergoing cardiac surgery (PROMETHEUS) trial. In: Circulation research. 2014 ; Vol. 114, No. 8. pp. 1302-1310.
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title = "Autologous mesenchymal stem cells produce concordant improvements in regional function, tissue perfusion, and fibrotic burden when administered to patients undergoing coronary artery bypass grafting: The prospective randomized study of mesenchymal stem cell therapy in patients undergoing cardiac surgery (PROMETHEUS) trial",
abstract = "Rationale: Although accumulating data support the efficacy of intramyocardial cell-based therapy to improve left ventricular (LV) function in patients with chronic ischemic cardiomyopathy undergoing CABG, the underlying mechanism and impact of cell injection site remain controversial. Mesenchymal stem cells (MSCs) improve LV structure and function through several effects including reducing fibrosis, neoangiogenesis, and neomyogenesis. Objective: To test the hypothesis that the impact on cardiac structure and function after intramyocardial injections of autologous MSCs results from a concordance of prorecovery phenotypic effects. Methods and results: Six patients were injected with autologous MSCs into akinetic/hypokinetic myocardial territories not receiving bypass graft for clinical reasons. MRI was used to measure scar, perfusion, wall thickness, and contractility at baseline, at 3, 6, and 18 months and to compare structural and functional recovery in regions that received MSC injections alone, revascularization alone, or neither. A composite score of MRI variables was used to assess concordance of antifibrotic effects, perfusion, and contraction at different regions. After 18 months, subjects receiving MSCs exhibited increased LV ejection fraction (+9.4±1.7{\%}, P=0.0002) and decreased scar mass (-47.5±8.1{\%}; P<0.0001) compared with baseline. MSC-injected segments had concordant reduction in scar size, perfusion, and contractile improvement (concordant score: 2.93±0.07), whereas revascularized (0.5±0.21) and nontreated segments (-0.07±0.34) demonstrated nonconcordant changes (P<0.0001 versus injected segments). Conclusions: Intramyocardial injection of autologous MSCs into akinetic yet nonrevascularized segments produces comprehensive regional functional restitution, which in turn drives improvement in global LV function. These findings, although inconclusive because of lack of placebo group, have important therapeutic and mechanistic hypothesis-generating implications. Clinical trial registration: URL: http://clinicaltrials.gov/show/NCT00587990. Unique identifier: NCT00587990.",
author = "Vasileios Karantalis and Difede, {Darcy L.} and Gary Gerstenblith and Si Pham and James Symes and Zambrano, {Juan Pablo} and Joel Fishman and Pradip Pattany and Ian McNiece and John Conte and Steven Schulman and Katherine Wu and Ashish Shah and Elayne Breton and Janice Davis-Sproul and Richard Schwarz and Gary Feigenbaum and Muzammil Mushtaq and Suncion, {Viky Y.} and Lardo, {Albert C.} and Ivan Borrello and Adam Mendizabal and Karas, {Tomer Z.} and John Byrnes and Maureen Lowery and Heldman, {Alan W.} and Hare, {Joshua M.}",
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doi = "10.1161/CIRCRESAHA.114.303180",
language = "English (US)",
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journal = "Circulation Research",
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Karantalis, V, Difede, DL, Gerstenblith, G, Pham, S, Symes, J, Zambrano, JP, Fishman, J, Pattany, P, McNiece, I, Conte, J, Schulman, S, Wu, K, Shah, A, Breton, E, Davis-Sproul, J, Schwarz, R, Feigenbaum, G, Mushtaq, M, Suncion, VY, Lardo, AC, Borrello, I, Mendizabal, A, Karas, TZ, Byrnes, J, Lowery, M, Heldman, AW & Hare, JM 2014, 'Autologous mesenchymal stem cells produce concordant improvements in regional function, tissue perfusion, and fibrotic burden when administered to patients undergoing coronary artery bypass grafting: The prospective randomized study of mesenchymal stem cell therapy in patients undergoing cardiac surgery (PROMETHEUS) trial', Circulation research, vol. 114, no. 8, pp. 1302-1310. https://doi.org/10.1161/CIRCRESAHA.114.303180

Autologous mesenchymal stem cells produce concordant improvements in regional function, tissue perfusion, and fibrotic burden when administered to patients undergoing coronary artery bypass grafting : The prospective randomized study of mesenchymal stem cell therapy in patients undergoing cardiac surgery (PROMETHEUS) trial. / Karantalis, Vasileios; Difede, Darcy L.; Gerstenblith, Gary; Pham, Si; Symes, James; Zambrano, Juan Pablo; Fishman, Joel; Pattany, Pradip; McNiece, Ian; Conte, John; Schulman, Steven; Wu, Katherine; Shah, Ashish; Breton, Elayne; Davis-Sproul, Janice; Schwarz, Richard; Feigenbaum, Gary; Mushtaq, Muzammil; Suncion, Viky Y.; Lardo, Albert C.; Borrello, Ivan; Mendizabal, Adam; Karas, Tomer Z.; Byrnes, John; Lowery, Maureen; Heldman, Alan W.; Hare, Joshua M.

In: Circulation research, Vol. 114, No. 8, 01.01.2014, p. 1302-1310.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Autologous mesenchymal stem cells produce concordant improvements in regional function, tissue perfusion, and fibrotic burden when administered to patients undergoing coronary artery bypass grafting

T2 - The prospective randomized study of mesenchymal stem cell therapy in patients undergoing cardiac surgery (PROMETHEUS) trial

AU - Karantalis, Vasileios

AU - Difede, Darcy L.

AU - Gerstenblith, Gary

AU - Pham, Si

AU - Symes, James

AU - Zambrano, Juan Pablo

AU - Fishman, Joel

AU - Pattany, Pradip

AU - McNiece, Ian

AU - Conte, John

AU - Schulman, Steven

AU - Wu, Katherine

AU - Shah, Ashish

AU - Breton, Elayne

AU - Davis-Sproul, Janice

AU - Schwarz, Richard

AU - Feigenbaum, Gary

AU - Mushtaq, Muzammil

AU - Suncion, Viky Y.

AU - Lardo, Albert C.

AU - Borrello, Ivan

AU - Mendizabal, Adam

AU - Karas, Tomer Z.

AU - Byrnes, John

AU - Lowery, Maureen

AU - Heldman, Alan W.

AU - Hare, Joshua M.

PY - 2014/1/1

Y1 - 2014/1/1

N2 - Rationale: Although accumulating data support the efficacy of intramyocardial cell-based therapy to improve left ventricular (LV) function in patients with chronic ischemic cardiomyopathy undergoing CABG, the underlying mechanism and impact of cell injection site remain controversial. Mesenchymal stem cells (MSCs) improve LV structure and function through several effects including reducing fibrosis, neoangiogenesis, and neomyogenesis. Objective: To test the hypothesis that the impact on cardiac structure and function after intramyocardial injections of autologous MSCs results from a concordance of prorecovery phenotypic effects. Methods and results: Six patients were injected with autologous MSCs into akinetic/hypokinetic myocardial territories not receiving bypass graft for clinical reasons. MRI was used to measure scar, perfusion, wall thickness, and contractility at baseline, at 3, 6, and 18 months and to compare structural and functional recovery in regions that received MSC injections alone, revascularization alone, or neither. A composite score of MRI variables was used to assess concordance of antifibrotic effects, perfusion, and contraction at different regions. After 18 months, subjects receiving MSCs exhibited increased LV ejection fraction (+9.4±1.7%, P=0.0002) and decreased scar mass (-47.5±8.1%; P<0.0001) compared with baseline. MSC-injected segments had concordant reduction in scar size, perfusion, and contractile improvement (concordant score: 2.93±0.07), whereas revascularized (0.5±0.21) and nontreated segments (-0.07±0.34) demonstrated nonconcordant changes (P<0.0001 versus injected segments). Conclusions: Intramyocardial injection of autologous MSCs into akinetic yet nonrevascularized segments produces comprehensive regional functional restitution, which in turn drives improvement in global LV function. These findings, although inconclusive because of lack of placebo group, have important therapeutic and mechanistic hypothesis-generating implications. Clinical trial registration: URL: http://clinicaltrials.gov/show/NCT00587990. Unique identifier: NCT00587990.

AB - Rationale: Although accumulating data support the efficacy of intramyocardial cell-based therapy to improve left ventricular (LV) function in patients with chronic ischemic cardiomyopathy undergoing CABG, the underlying mechanism and impact of cell injection site remain controversial. Mesenchymal stem cells (MSCs) improve LV structure and function through several effects including reducing fibrosis, neoangiogenesis, and neomyogenesis. Objective: To test the hypothesis that the impact on cardiac structure and function after intramyocardial injections of autologous MSCs results from a concordance of prorecovery phenotypic effects. Methods and results: Six patients were injected with autologous MSCs into akinetic/hypokinetic myocardial territories not receiving bypass graft for clinical reasons. MRI was used to measure scar, perfusion, wall thickness, and contractility at baseline, at 3, 6, and 18 months and to compare structural and functional recovery in regions that received MSC injections alone, revascularization alone, or neither. A composite score of MRI variables was used to assess concordance of antifibrotic effects, perfusion, and contraction at different regions. After 18 months, subjects receiving MSCs exhibited increased LV ejection fraction (+9.4±1.7%, P=0.0002) and decreased scar mass (-47.5±8.1%; P<0.0001) compared with baseline. MSC-injected segments had concordant reduction in scar size, perfusion, and contractile improvement (concordant score: 2.93±0.07), whereas revascularized (0.5±0.21) and nontreated segments (-0.07±0.34) demonstrated nonconcordant changes (P<0.0001 versus injected segments). Conclusions: Intramyocardial injection of autologous MSCs into akinetic yet nonrevascularized segments produces comprehensive regional functional restitution, which in turn drives improvement in global LV function. These findings, although inconclusive because of lack of placebo group, have important therapeutic and mechanistic hypothesis-generating implications. Clinical trial registration: URL: http://clinicaltrials.gov/show/NCT00587990. Unique identifier: NCT00587990.

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DO - 10.1161/CIRCRESAHA.114.303180

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