Infarct Remodeling After Intracoronary Progenitor Cell Treatment in Patients With Acute Myocardial Infarction (TOPCARE-AMI)

Britten, Martina; Abolmaali, Nasreddin; Aßmus, Birgit; Lehmann, Ralf; Honold, Joerg; Schmitt, J.; Vogl, Thomas J.; Martin, Hans; Schächinger, Volker; Dimmeler, Stefanie; Zeiher, Andreas M.

doi:10.1161/01.cir.0000095788.78169.af

Cited by 500 publications

(114 citation statements)

References 38 publications

(40 reference statements)

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“…Moreover, the demonstration that GFs induce translocation of resident progenitor cells to the infarct, rebuilding the lost myocardium in larger mammals, closes the gap between rodents and humans and strengthens the feasibility and applicability of local stem cell activation in the patient population. This strategy is minimally invasive and avoids the complication of rejection and the effects of time on the onset of therapy linked to the acquisition and in vitro expansion of the patient's own progenitor cells (24,25). Additionally, the risks inherent in the systemic mobilization of a large number of hematopoietic and other stem cells to nontarget organs are prevented.…”

Section: Discussionmentioning

confidence: 99%

Stem cells in the dog heart are self-renewing, clonogenic, and multipotent and regenerate infarcted myocardium, improving cardiac function

Linke

Müller

Nurzynska

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

527

386

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The purpose of this study was to determine whether the heart in large mammals contains cardiac progenitor cells that regulate organ homeostasis and regenerate dead myocardium after infarction. We report that the dog heart possesses a cardiac stem cell pool characterized by undifferentiated cells that are self-renewing, clonogenic, and multipotent. These clonogenic cells and early committed progeny possess a hepatocyte growth factor (HGF)-cMet and an insulin-like growth factor 1 (IGF-1)-IGF-1 receptor system that can be activated to induce their migration, proliferation, and survival. Therefore, myocardial infarction was induced in chronically instrumented dogs implanted with sonomicrometric crystals in the region of the left ventricular wall supplied by the occluded left anterior descending coronary artery. After infarction, HGF and IGF-1 were injected intramyocardially to stimulate resident cardiac progenitor cells. This intervention led to the formation of myocytes and coronary vessels within the infarct. Newly generated myocytes expressed nuclear and cytoplasmic proteins specific of cardiomyocytes: MEF2C was detected in the nucleus, whereas ␣-sarcomeric actin, cardiac myosin heavy chain, troponin I, and ␣-actinin were identified in the cytoplasm. Connexin 43 and N-cadherin were also present. Myocardial reconstitution resulted in a marked recovery of contractile performance of the infarcted heart. In conclusion, the activation of resident primitive cells in the damaged dog heart can promote a significant restoration of dead tissue, which is paralleled by a progressive improvement in cardiac function. These results suggest that strategies capable of activating the growth reserve of the myocardium may be important in cardiac repair after ischemic injury.cardiac stem cells ͉ myocardial infarction ͉ myocardial regeneration

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Section: Discussionmentioning

confidence: 99%

Stem cells in the dog heart are self-renewing, clonogenic, and multipotent and regenerate infarcted myocardium, improving cardiac function

Linke

Müller

Nurzynska

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

527

386

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“…Several cell types have been used in an effort to reconstitute dead myocardium. Among them, endothelial progenitor cells and bone marrow-derived cells have been the most successful (2)(3)(4)(5)(6). However, preliminary long-term studies with bone marrow-derived cells indicate that the new myocytes do not acquire the adult phenotype but resemble neonatal cells, which die with time by apoptosis (P.A., unpublished data).…”

mentioning

confidence: 99%

Cardiac stem cells delivered intravascularly traverse the vessel barrier, regenerate infarcted myocardium, and improve cardiac function

Dawn

Stein

Urbanek

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

433

316

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The ability of cardiac stem cells (CSCs) to promote myocardial repair under clinically relevant conditions (i.e., when delivered intravascularly after reperfusion) is unknown. Thus, rats were subjected to a 90-min coronary occlusion; at 4 h after reperfusion, CSCs were delivered to the coronary arteries via a catheter positioned into the aortic root. Echocardiographic analysis showed that injection of CSCs attenuated the increase in left ventricular (LV) end-diastolic dimensions and impairment in LV systolic performance at 5 weeks after myocardial infarction. Pathologic analysis showed that treated hearts exhibited a smaller increase in LV chamber diameter and volume and a higher wall thickness-to-chamber radius ratio and LV mass-to-chamber volume ratio. CSCs induced myocardial regeneration, decreasing infarct size by 29%. A diploid DNA content and only two chromosomes 12 were found in new cardiomyocytes, indicating that cell fusion did not contribute to tissue reconstitution. In conclusion, intravascular injection of CSCs after reperfusion limits infarct size, attenuates LV remodeling, and ameliorates LV function. This study demonstrates that CSCs are effective when delivered in a clinically relevant manner, a clear prerequisite for clinical translation, and that these beneficial effects are independent of cell fusion. The results establish CSCs as candidates for cardiac regeneration and support an approach in which the heart's own stem cells could be collected, expanded, and stored for subsequent therapeutic repair. myocardial infarction ͉ myocardial regeneration W ith the recent surge of interest in cardiac regenerative therapies for patients with acute myocardial infarction (MI) (1), the identification of clinically applicable strategies is of paramount importance. Several cell types have been used in an effort to reconstitute dead myocardium. Among them, endothelial progenitor cells and bone marrow-derived cells have been the most successful (2-6). However, preliminary long-term studies with bone marrow-derived cells indicate that the new myocytes do not acquire the adult phenotype but resemble neonatal cells, which die with time by apoptosis (P.A., unpublished data). Intense efforts continue to focus on identifying an effective cell population and an effective mode of delivery.The discovery that the adult heart contains a pool of cardiac stem cells (CSCs) that can replenish the cardiomyocyte population and generate coronary vessels (7-12) has dramatically changed the traditional view of the heart as a postmitotic organ. Because of its natural role in regeneration of cardiac cells, the endogenous CSC appears to be the ideal cell for myocardial repair. Recent studies have shown that when c-kit POS CSCs are injected directly into the myocardium adjacent to an infarct produced by a permanent coronary occlusion, they migrate to the infarct and reconstitute part of the dead tissue, reducing infarct size and ameliorating cardiac function in rats (9) and mice (12). In contrast, i.v. injection of CSCs in mice subje...

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“…[39][40][41] We used Lymphoprep for BMMNC isolation and included heparin in our isolation protocol, which is similar to previous studies that showed potential clinical effects. 13,38,42 Heparin has been reported to negatively affect cellular homing by impairment of the SDF-1α/CXCR4 axis. 40 We cannot exclude that the use of heparin in our isolation procedure could have reduced the potency of our product.…”

Section: Discussionmentioning

confidence: 99%

Effect of Repetitive Intra-Arterial Infusion of Bone Marrow Mononuclear Cells in Patients With No-Option Limb Ischemia

Teraa¹,

Sprengers²,

Schutgens³

et al. 2015

Circulation

157

103

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Background— Patients with severe limb ischemia may not be eligible for conventional therapeutic interventions. Pioneering clinical trials suggest that bone marrow–derived cell therapy enhances neovascularization, improves tissue perfusion, and prevents amputation. The objective of this trial was to determine whether repetitive intra-arterial infusion of bone marrow mononuclear cells (BMMNCs) in patients with severe, nonrevascularizable limb ischemia can prevent major amputation. Methods and Results— The Rejuvenating Endothelial Progenitor Cells via Transcutaneous Intra-arterial Supplementation (JUVENTAS) trial is a randomized, double-blind, placebo-controlled clinical trial in 160 patients with severe, nonrevascularizable limb ischemia. Patients were randomly assigned to repetitive (3 times; 3-week interval) intra-arterial infusion of BMMNC or placebo. No significant differences were observed for the primary outcome, ie, major amputation at 6 months, with major amputation rates of 19% in the BMMNC versus 13% in the placebo group (relative risk, 1.46; 95% confidence interval, 0.62–3.42). The safety outcome (all-cause mortality, occurrence of malignancy, or hospitalization due to infection) was not significantly different between the groups (relative risk, 1.46; 95% confidence interval, 0.63–3.38), neither was all-cause mortality at 6 months with 5% versus 6% (relative risk, 0.78; 95% confidence interval, 0.22–2.80). Secondary outcomes quality of life, rest pain, ankle-brachial index, and transcutaneous oxygen pressure improved during follow-up, but there were no significant differences between the groups. Conclusions— Repetitive intra-arterial infusion of autologous BMMNCs into the common femoral artery did not reduce major amputation rates in patients with severe, nonrevascularizable limb ischemia in comparison with placebo. The general improvement in secondary outcomes during follow-up in both the BMMNC and the placebo group, as well, underlines the essential role for placebo-controlled design of future trials. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00371371.

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Infarct Remodeling After Intracoronary Progenitor Cell Treatment in Patients With Acute Myocardial Infarction (TOPCARE-AMI)

Cited by 500 publications

References 38 publications

Stem cells in the dog heart are self-renewing, clonogenic, and multipotent and regenerate infarcted myocardium, improving cardiac function

Stem cells in the dog heart are self-renewing, clonogenic, and multipotent and regenerate infarcted myocardium, improving cardiac function

Cardiac stem cells delivered intravascularly traverse the vessel barrier, regenerate infarcted myocardium, and improve cardiac function

Effect of Repetitive Intra-Arterial Infusion of Bone Marrow Mononuclear Cells in Patients With No-Option Limb Ischemia

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