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Echocardiographic evaluation of the effects of stem cell therapy on perfusion and function in ischemic cardiomyopathy.

ABSTRACT: Small animal models of ischemic left ventricular (LV) dysfunction are important for the preclinical optimization of stem cell therapy. The aim of this study was to test the hypothesis that temporal changes in LV function and regional perfusion after cell therapy can be assessed in mice using echocardiographic imaging.Wild-type mice (n = 25) were studied 7 and 28 days after permanent ligation of the left anterior descending coronary artery. Animals were randomized to receive closed-chest ultrasound-guided intramyocardial delivery of saline (n = 13) or 5 × 10(5) multipotential adult progenitor cells (MAPCs; n = 12) on day 7. LV end-diastolic and end-systolic volumes, LV ejection fraction, and stroke volume were measured using high-frequency echocardiography. Multiplanar assessments of perfusion and defect area size were made using myocardial contrast echocardiography.Between days 7 and 28, MAPC-treated animals had 40% to 50% reductions in defect size (P < .001) and 20% to 30% increases in total perfusion (P < .01). Perfusion did not change in nontreated controls. Both LV end-diastolic and end-systolic volumes increased between days 7 and 28 in both groups, but LV end-systolic volume increased to a lesser degree in MAPC-treated compared with control mice (+4.2 ± 7.9 vs +19.2 ± 22.0 ?L, P < .05). LV ejection fraction increased in the MAPC-treated mice and decreased in control mice (+3.0 ± 4.3% vs -5.6 ± 5.9%, P < .01). There was a significant linear relation between the change in LV ejection fraction and the change in either defect area size or total perfusion.High-frequency echocardiography and myocardial contrast echocardiography in murine models of ischemic LV dysfunction can be used to assess the response to stem cell therapy and to characterize the relationship among spatial flow, ventricular function, and ventricular remodeling.

SUBMITTER: Inaba Y

PROVIDER: S-EPMC3946830 | biostudies-literature | 2014 Feb

REPOSITORIES: biostudies-literature

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Echocardiographic evaluation of the effects of stem cell therapy on perfusion and function in ischemic cardiomyopathy.

Inaba Yoichi Y Davidson Brian P BP Kim Sajeevani S Liu Ya Ni YN Packwood William W Belcik J Todd JT Xie Aris A Lindner Jonathan R JR

Journal of the American Society of Echocardiography : official publication of the American Society of Echocardiography 20131204 2

<h4>Background</h4>Small animal models of ischemic left ventricular (LV) dysfunction are important for the preclinical optimization of stem cell therapy. The aim of this study was to test the hypothesis that temporal changes in LV function and regional perfusion after cell therapy can be assessed in mice using echocardiographic imaging.<h4>Methods</h4>Wild-type mice (n = 25) were studied 7 and 28 days after permanent ligation of the left anterior descending coronary artery. Animals were randomiz ...[more]

PMID: 24315764

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Project description:BACKGROUND:Cell therapy with bone marrow (BM)-derived progenitors has emerged as a promising therapeutic for refractory angina (RA) patients. In the present study, we evaluated the safety and preliminary efficacy of transcatheter delivery of autologous BM-derived advanced therapy medicinal product CD133+ cells (ATMP-CD133) in RA patients, correlating perfusion outcome with cell function. METHODS:In the phase I "Endocavitary Injection of Bone Marrow Derived CD133+ Cells in Ischemic Refractory Cardiomyopathy" (RECARDIO) trial, a total of 10 patients with left ventricular (LV) dysfunction (ejection fraction ??45%) and evidence of reversible ischemia, as assessed by single-photon emission computed tomography (SPECT), underwent BM aspiration and fluoroscopy-based percutaneous endomyocardial delivery of ATMP-CD133. Patients were evaluated at 6 and 12 months for safety and preliminary efficacy endpoints. ATMP-CD133 samples were used for in vitro correlations. RESULTS:Patients were treated safely with a mean number of 6.57?±?3.45?×? 106 ATMP-CD133. At 6-month follow-up, myocardial perfusion at SPECT was significantly ameliorated in terms of changes in summed stress (from 18.2?±?8.6 to 13.8?±?7.8, p?=?0.05) and difference scores (from 12.0?±?5.3 to 6.1?±?4.0, p?=?0.02) and number of segments with inducible ischemia (from 7.3?±?2.2 to 4.0?±?2.7, p?=?0.003). Similarly, Canadian Cardiovascular Society and New York Heart Association classes significantly improved at follow-up vs baseline (p???0.001 and p?=?0.007, respectively). Changes in summed stress score changes positively correlated with ATMP-CD133 release of proangiogenic cytokines HGF and PDGF-bb (r?=?0.80, p?=?0.009 and r?=?0.77, p?=?0.01, respectively) and negatively with the proinflammatory cytokines RANTES (r?=?-?0.79, p?=?0.01) and IL-6 (r?=?-?0.76, p?=?0.02). CONCLUSION:Results of the RECARDIO trial suggested safety and efficacy in terms of clinical and perfusion outcomes in patients with RA and LV dysfunction. The observed link between myocardial perfusion improvements and ATMP-CD133 secretome may represent a proof of concept for further mechanistic investigations. TRIAL REGISTRATION:ClinicalTrials.gov, NCT02059681 . Registered 11 February 2014.

Project description:BACKGROUND:Ischemic cardiomyopathy (ICM) and dilated cardiomyopathy (DCM) differ in histopathology and prognosis. Although transendocardial delivery of mesenchymal stem cells is safe and provides cardiovascular benefits in both, a comparison of mesenchymal stem cell efficacy in ICM versus DCM has not been done. METHODS AND RESULTS:We conducted a subanalysis of 3 single-center, randomized, and blinded clinical trials: (1) TAC-HFT (Transendocardial Autologous Mesenchymal Stem Cells and Mononuclear Bone Marrow Cells in Ischemic Heart Failure Trial); (2) POSEIDON (A Phase I/II, Randomized Pilot Study of the Comparative Safety and Efficacy of Transendocardial Injection of Autologous Mesenchymal Stem Cells Versus Allogeneic Mesenchymal Stem Cells in Patients With Chronic Ischemic Left Ventricular Dysfunction Secondary to Myocardial Infarction); and (3) POSEIDON-DCM (Percutaneous Stem Cell Injection Delivery Effects on Neomyogenesis in Dilated Cardiomyopathy). Baseline and 1-year cardiac structure and function and quality-of-life data were compared in a post hoc pooled analysis including ICM (n=46) and DCM (n=33) patients who received autologous or allogeneic mesenchymal stem cells. Ejection fraction improved in DCM by 7% (within-group, P=0.002) compared to ICM (1.5%; within-group, P=0.14; between-group, P=0.003). Similarly, stroke volume increased in DCM by 10.59 mL (P=0.046) versus ICM (-0.2 mL; P=0.73; between-group, P=0.02). End-diastolic volume improved only in ICM (10.6 mL; P=0.04) and end-systolic volume improved only in DCM (17.8 mL; P=0.049). The sphericity index decreased only in ICM (-0.04; P=0.0002). End-diastolic mass increased in ICM (23.1 g; P<0.0001) versus DCM (-4.1 g; P=0.34; between-group, P=0.007). The 6-minute walk test improved in DCM (31.1 m; P=0.009) and ICM (36.3 m; P=0.006) with no between-group difference (P=0.79). The New York Heart Association class improved in DCM (P=0.005) and ICM (P=0.02; between-group P=0.20). The Minnesota Living with Heart Failure Questionnaire improved in DCM (-19.5; P=0.002) and ICM (-6.4; P=0.03; ? between-group difference P=0.042) patients. CONCLUSIONS:Mesenchymal stem cell therapy is beneficial in DCM and ICM patients, despite variable effects on cardiac phenotypic outcomes. Whereas cardiac function improved preferentially in DCM patients, ICM patients experienced reverse remodeling. Mesenchymal stem cell therapy enhanced quality of life and functional capacity in both etiologies. CLINICAL TRIAL REGISTRATION:URL: http://www.clinicaltrials.gov. Unique identifiers: TAC-HFT: NCT00768066, POSEIDON: NCT01087996, POSEIDON-DCM: NCT01392625.

Dataset Information

Echocardiographic evaluation of the effects of stem cell therapy on perfusion and function in ischemic cardiomyopathy.

Publications

Echocardiographic evaluation of the effects of stem cell therapy on perfusion and function in ischemic cardiomyopathy.

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