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Trans-coronary transplantation may be an optimal route in cellular cardiomyoplasty with stem cells
Medical Hypotheses (2007) 69, 1212–1218
http://intl.elsevierhealth.com/journals/mehy
Trans-coronary transplantation may be an optimal route in cellular cardiomyoplasty with stem cells Zhi-Zhong Li
a,*
, Shu-Gong Bai a, Ji Huang
a,b
, Hai-Yan Qian
c
a
Emergency Center of Heart, Lung and Blood Vessel Diseases, Beijing Anzhen Hospital, Capital University of Medical Sciences and Beijing Institute of Heart, Lung and Blood Vessel Diseases, An Zhen Li, An Ding Men Wai, Chao Yang District, Beijing 100029, PR China b Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, PR China c Department of Cardiology, Fuwai Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100037, PR China Received 16 March 2007; accepted 17 April 2007
Summary Myocardial infarction is the leading cause of congestive heart failure and death in the industrialized world. However, the intrinsic repair mechanism of the injured heart and current therapeutic means are inadequate to regenerate lost myocardium. Recent interests focused on cellular cardiomyoplasty which is an outside intervention to support the reparative process in the heart through transplantation of stem/progenitor cells. Cellular myocardioplasty with stem cells is a possible option to reverse the adverse hemodynamic and neurohormonal imbalance after myocardial infarction. Experimental studies and clinical trials suggest that cellular cardiomyoplasty with stem/ progenitor cells may improve cardiac function and prevent ventricular remodeling of the injured heart. Although the mechanisms are still in intensive debate, cellular cardiomyoplasty with stem cells has already been introduced into the clinical settings. However, it is an important challenge how donor cells are delivered to the targeted area. In early studies in animals, intramyocardial injection of stem cells after thoracotomy is the main transplantation route which is not suitable to most patients in clinical settings. Then the catheter-based infusion of stem cells is clinically introduced and rapidly developed because of its safety, convenience and micro-invasion. We hypothesize that catheter-based transplantation with stem cells may be a promising means to treat ischemic heart diseases in the future in clinical settings. c 2007 Elsevier Ltd. All rights reserved.
Introduction and hypothesis Myocardial infarction (MI) is the leading cause of congestive heart failure (CHF) and death in the
* Corresponding author. Tel.: +86 10 64456200. E-mail address: [email protected] (Z.-Z. Li).
industrialized world [1]. Although there have been great advances in cardiovascular therapeutics, treatment of ischemic heart diseases (IHD) remains an important challenge. Current therapeutic means focus on ameliorating the progression of ventricular remodeling and subsequent heart failure, but incapable of regenerating the lost cardiomyocytes caused by necrosis and apoptosis. Recent evidence
0306-9877/$ - see front matter c 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.mehy.2007.04.013
Trans-coronary transplantation may be an optimal route in cellular cardiomyoplasty with stem cells
has been presented that human myocardium can reenter the cell-cycle and divide after acute myocardial infarction (AMI), but this intrinsic repair capacity is too weak to substantially regenerate infarcted cardiomyocytes [2,3]. Therefore, it is necessary to develop a new method to promote myocardium regeneration. The discovery of plasticity of adult stem cell may bring about a breakthrough in treatment of MI. Stem cells are capable of self-renewal and differentiation to specialized progeny. Traditional standpoint is that tissue-resident adult stem cells only can differentiate into special kind of progeny. Plasticity indicates that stem cells can transdifferentiate into other cell types outside their original tissues under certain conditions [4–6]. Based on the advances in stem cell research, there has been a new method in cardiovascular therapeutics in recent years, named as cellular cardiomyoplasty (CCM), which is an outside intervention to support the reparative process in the heart through transplantation of stem/progenitor cells or cardiac cells, or mobilizing peripheral blood- or bone marrow-derived stem cells into the site of cardiac injury. CCM with stem cells is a possible option to reverse the deleterious hemodynamic and neurohormonal effects after MI; various preclinical animal studies show the potential of stem cells to regenerate myocardium, improve perfusion of the infarcted area and improve cardiac function [7–9]. Early phase I clinical studies indicate that transplantation of stem cells is feasible and may have beneficial effects on ventricular remodeling after MI [10–15]. Although several studies indicated that bone marrow-derived stem cells did not have the potential to transdifferentiate into cardiomyocytes in vitro and in vivo [16,17], most of other experimental studies suggested that implanted stem cells could transdifferentiate into cardiomyocytes, vascular smooth muscle cells and endothelial cells, decrease apoptosis of hypertrophied myocytes in the peri-infarction region, decrease size of fibrosis scar, enhance myocardial blood flow so as to improve perfusion, rescue hibernating myocardium, excrete cytokines or growth factors causing proliferation of endogenous cardiac myocytes and enhance resident cardiac stem cell function [18–23]. However, it is an important challenge how donor cells are delivered to the targeted area. In early studies in animals, intramyocardial injection of stem cells after thoracotomy is the predominant transplantation route which is not suited to most patients in clinical settings. Then the catheterbased infusion of stem cells is clinically introduced and rapidly developed because of its safety, conve-
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nience and micro-invasion. We hypothesize that catheter-based transplantation with stem cells may be a promising means to treat ischemic heart diseases in the future in clinical settings.
Intracoronary infusion of stem cells Feasibility The main objective of various cell delivery approaches is to implant sufficient numbers of cells into the target area of myocardium and to keep maximum retention of cells within that area. Previous animal experiments and clinical studies demonstrated that several delivery routes of stem cells, including intramyocardial injection after thoracotomy, percutaneous catheter-based injection (intramyocardial injection and intravascular injection) and trans-peripheral-vascular route, were effective and safe. Among others, catheter-based transplantation of stem cells was especially the focus of interest. Since Strauer et al. [24] for the first time successfully transplanted bone marrow-derived mononuclear cells to treat patients with AMI by transcoronary infusion in 2002, studies by intracoronary infusion have been rising in animal experiments and clinical studies. Most of these studies demonstrated that intracoronary infusion of various stem cells was safe and effective to IHD. In these studies, cells were delivered through the over-the-wire balloon catheter during transient balloon inflations to maximize the contact time of the cells with the vascular walls of the infarct-related area. Intracoronary infusion is quite easy to perform in several minutes because of its familiarity by clinical cardiologists, which is advantageous over intravenous infusion because it can deliver the relatively more cells to the target area during the balloon inflations. Infusion in the infarct-related artery allows the stem cells to transmigrate the vascular walls into the peri-infarct zone, which differ from intramyocardial injection that may lead to disperse islands of cells in the infarct-related zone, providing a substrate for arrhythmias. Intracoronary infusion of stem cells is especially suited for the local microenvironment in which some beneficial cytokines are highly expressed, severely inflammatory reactions subside to avoid killing implanted cells, and fibrous scar is not yet formed that may lead to the disconnection between implanted cells and host cardiomyocytes. However, the percentage of infused cells by intracoronary delivery migrating into the targeted area is not clear. In 2005, Hofmann et al. [25] for
1214 the first time clinically transplanted unselected bone marrow cells (BMCs) and CD34+ cells labeled with 18F-fluoro-deoxy-glucose (18F-FDG) by intracoronary delivery. Positron emission tomography imaging showed that 1.3–2.6% of BMCs were detected in the infarcted myocardium; the remaining activity was found primarily in liver and spleen. Regarding CD34+ cells, 14–39% of the total radioactivity was detected in the infarcted myocardium. This study demonstrated that the donor cells which were transplanted by intracoronary infusion did actually engraft into the post-infarction myocardium to restore the injured heart. In addition, recent study reported by Qian et al. [26] demonstrated that 6.8 ± 1.8% of bone marrowmononuclear cells radiolabeled by 18F-FDG engrafted into the post-infarction myocardium at 1 h after being intracoronarily delivered, and the retention rate of labeled cells in the myocardium was positively correlated with the size of underperfused area.
Safety It is the most important issue whether intracoronary infusion of stem cells is safe. Up to date, most of the animal experiments and clinical trials have demonstrated that intracoronary transplantation of stem cells is safe. However, there still have been the following studies indicating that several unexpected situations were possibly complicated with this transcatheter procedure. First, Vulliet et al. [27] showed that intracoronary infusion of bone marrow-derived mesenchymal stem cells (MSCs) caused microinfarction in healthy dogs, which for the first time raised caution to the safety of intracoronary infusion. Second, Van derheyden et al. [28] found that intracoronary infusion stem cells accelerated atherogenesis progress in an AMI patient. However, this is a single case report which is not representative. Third, Kang et al. [29] showed granulocyte-colony stimulating factor (G-CSF) administration associated with intracoronary infusion of circulating stem cells improved cardiac function, and promoted angiogenesis in patients with MI. However, an unexpectedly high rate of in-stent restenosis (ISR) at culprit lesion in patients who received G-CSF was observed. In addition, Steinwender et al. [30] sought to evaluate a clinical and angiographic long-term safety profile of G-CSF application combined with transcoronary transplantation of peripheral blood stem cells (PBSC) after recent stent implantation for AMI.
Li et al. After 6 months, in the 20 patients who received PBSCs transplantation, mean left ventricular ejection fraction (LVEF) improved from 46.4 ± 8.1% at baseline to 54.3 ± 11% (P < 0.001). Control coronary angiography revealed a significant in-stent restenosis of the infarct-related coronary artery, defined as >50% stenosis, in eight patients (40%), which was complicated by reinfarction in two patients (10%). These findings indicated that transcoronary transplantation of G-CSF-mobilized PBSCs favorably influences cardiac function and can be performed without adverse periprocedural events. However, significant in-stent restenosis and reinfarction seem to occur frequently during the following 6 months. Similarly, Inoue et al. [31] also found that in 40 patients undergoing coronary stenting, after baremetal stenting, circulating CD34-positive cells increased, reaching a maximum on day 7 after stenting. Cell culture assay on day 7 showed that mononuclear cells differentiated into endothelium-like cells after bare-metal stenting. In patients with restenosis, mononuclear cells differentiating into smooth muscle-like cells also were observed. These results indicated that stent implantation may induce differentiation of bone marrow cells into endothelial or smooth muscle cells. Endothelial cells may participate in re-endothelialization, a protective reaction against vascular injury, whereas smooth muscle cells may participate in neointimal thickening and restenosis. Regarding the possible increase in in-stent restenosis following stem cell infusion, there are three reasons to interpret: (1) improper procedure during the infusion because of the balloon inflation possibly result in more significant stimulations to the damaged vessel wall; (2) mononuclear cells contain several types of stem cells as well as pro-inflammatory cells which may adhere to the stent-implanting segment of vascular wall; (3) several chemotatic factors, such as G-CSF, can attract circulating inflammatory cells engrafting into the stent-implanting vessel wall, which then trigger inflammatory reaction; (4) the inflammatory response after vascular injury triggers the mobilization of smooth muscle progenitor cells from bone marrow to differentitate into smooth muscle cells accumulating in the neo-intima. Even though above findings do exist, other similar investigations did not find the similar results. Moreover, most of current studies on animals and patients have not found other adverse events complicated with intracoronary infusion of stem cells, such as tumorigenesis, arrhythmias and functional exacerbation.
Trans-coronary transplantation may be an optimal route in cellular cardiomyoplasty with stem cells
Effectiveness Another important issue involved in intracoronary infusion of stem cells is whether it is effective on post-infarction or other injured hearts. Over the last 5 years, several clinical studies published have used autologous bone marrow as well as peripheral blood-derived progenitor cells, which were transplanted via intracoronary infusion to the ischemic area. The initial results demonstrated the safety and benefit of this strategy, which appears to be relatively inexpensive and free of side effects. Up to today, several clinical trials have already demonstrated that intracoronary infusions of adult stem or progenitor cells are effective on patients with AMI, old MI, ischemic cardiomyopathy and heart failure, including improvement in LVEF, inhibition of ventricular remodeling, decrease of infarcted area and cardiac apoptosis, inhibition of inflammatory response, prevention of cardiac fibrosis, promotion of angiogenesis, and secreting cytokines by paracrine mechanism, etc. [7–15]. In addition, Katritsis et al. [32] found that intracoronary transplantation of MSCs and endothelial progenitor cells (EPCs) did not appear to be arrhythmogenic, even mitigated the bout of ventricular arrhythmias, in five patients with a history of previous anteroseptal MI and ICD implant for ventricular arrhythmias underwent. Schueller et al. [33] found that intracoronary infusion of bone marrow cells beneficially increased heart rate variability in patients with transmural MI after three to twelve months of follow up. These findings further extended the practical applications for intracoronary infusion of stem cells in clinical settings.
Donor cell types Up to date, there have been many types of stem cells used to treat cardiovascular diseases by transcoronary infusion, including bone marrow- or peripheral blood-derived mononuclear cells [34,35], AC133+ cells [36] and CD34+ cells [37], bone marrow-derived MSCs [38], unfractionated BMCs [39], EPCs [40]. Previous studies related to CCM with stem cells are involved in almost all of IHD, such as AMI [41], ischemic cardiomyopathy [42], chronic total obstruction of coronary artery [35] and OMI [43].
Timing window of transplantation It is an important involvement when intracoronary infusion of stem cells is most effective, which ex-
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erts remarkable impacts on engraftment, survival and bioactivities of implanted cells in vivo. However, there have been the least studies to investigate that. Currently, there are several different standpoints about the optimal timing window of transplantation: (1) Early infusion, which means that intracoronary infusion is performed from immediate AMI to 1-week post-infarction. Theoretically, the inflammatory reactions are so intense during this period that the microenvironments in the post-infarction myocardium are unsuitable for implanted cells to survive and exert their bioactivities in vivo. Li et al. [44] reported that 2 weeks after AMI is the optimal timing for transplantation, which was better than immediate and 4-week post-AMI. The study reported by Janssens et al. [45] and REPAIR trial [46] indicated that transplantation of stem cells during 24 h after AMI had no functional benefits. In contrast, Ge et al. [47] for the first time demonstrated that early intracoronary infusion of bone marrow-mononuclear cells in patients within 24 h after AMI resulted in a significant increase in LVEF and prevented left ventricular dilation at 6-month follow-up. (2) Intermediate-stage transplantation, which means the period from 1-week post-infarction to not shaping of fibrotic scar. During this period, inflammatory reactions gradually subside and infarct-scar is not formed yet, therefore, the implanted cells can survive and act better. Currently, most of the clinical trials have been performed within this period. (3) Delayed transplantation, indicating that fibrotic scar has already formed in infarcted region. During this period, infarcted region is not suitable for the implanted cells to survive and limits the connections between donor cells and host myocardium, thus supplying a substrate of arrhythmias. However, IACT trial [43] indicated that intracoronary infusion of stem cells in patients with OMI caused a reduction by 30% in MI area, an increase by 57% in ventricular wall motion velocity in infarcted region and by 15% in LVEF, accompanied by improvement in exercise tolerance at 3-month follow-up. This study first demonstrated that intracoronary transplantation of stem cells during later-stage was still effective, thus extending the objects that are suitable to receive stem cells transplantation. Because of the differences in situations of included patients, follow-up, donor cell type, design of trials, etc., the results from above studies are different. Moreover, the milieu in the infarctedmyocardium is different in different situations of diseases and complicated diseases; therefore, the best timing window of transplantation should be individualized in single patient.
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Indications for intracoronary infusion of stem cells A portion of patients with AMI and ischemic cardiomyopathy had a great deal of stunning or hibernating myocardium which will restore their functions after successful revascularization. Subsequently, there will be significant improvements in cardiac function of these patients. Therefore, stem cell transplantation is not remarkably beneficial to these patients. Regarding those patients with AMI and ischemic cardiomyopathy whose cardiac function are still seriously damaged after revascularization, stem cell infusion is suitable. Furthermore, the more damage in cardiac function, the more effective is cell transplantation [14,48,49]. In addition, CHF complicated with dilated cardiomyopathy (DCM) is also the indications for stem cells transplantation. However, it is uncertain which situation of CHF is suitable to receive cell therapy. Agbulut et al. [50] for the first time demonstrated that intramyocardial injection of bone marrow-mononuclear cells was effective on mice with adriamycin-induced DCM. Their study suggested that stem cell transplantation is promising in the treatment of drug-induced cardiomyopathy or CHF.
Problems and perspective Intracoronary infusion of stem cells has been proven to be safe and effective to treat ischemic heart diseases in numerous animal experiments and clinical studies in recent years. However, there are still many problems to be resolved in the future study such as the following: (1) Does the plasticity really exist? And if it is true, what’s the molecular mechanism? (2) Which type, how many and which transplantation route of donor cells is the best? (3) What is the fate of donor cells in the post-infarction myocardium during long-term investigation? (4) How long does the short-term effectiveness originated from donor cells remain? (5) How does the dynamic distribution of intracoronarily delivered donor cells change in vivo? Notwithstanding, the mechanisms of CCM with stem cells are poorly understood, the exact homing mechanism and organ-specific differentiation signals for stem cells are not clearly understood, and fusion of transplanted stem cells with resident cardiomyocytes may be an alternative explanation for previous claims of transdifferentiation; it is interesting that cell therapy is already being introduced into the clinical settings. So far, most of the
Li et al. clinical studies related to CCM are small and uncontrolled. These studies have applied different tissue-derived cells to a small number of patients with different situations of IHD. Although these preclinical data indicate that CCM may be effective, we should carefully read these data. In the future, researches about CCM need to be largesample, long-term, double-blind, randomized-controlled clinical trials to reveal the actual effects of stem cell therapy in the real clinical application.
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Trans-coronary transplantation may be an optimal route in cellular cardiomyoplasty with stem cells Zhi-Zhong Li
a,*
, Shu-Gong Bai a, Ji Huang
a,b
, Hai-Yan Qian
c
a
Emergency Center of Heart, Lung and Blood Vessel Diseases, Beijing Anzhen Hospital, Capital University of Medical Sciences and Beijing Institute of Heart, Lung and Blood Vessel Diseases, An Zhen Li, An Ding Men Wai, Chao Yang District, Beijing 100029, PR China b Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, PR China c Department of Cardiology, Fuwai Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100037, PR China Received 16 March 2007; accepted 17 April 2007
Summary Myocardial infarction is the leading cause of congestive heart failure and death in the industrialized world. However, the intrinsic repair mechanism of the injured heart and current therapeutic means are inadequate to regenerate lost myocardium. Recent interests focused on cellular cardiomyoplasty which is an outside intervention to support the reparative process in the heart through transplantation of stem/progenitor cells. Cellular myocardioplasty with stem cells is a possible option to reverse the adverse hemodynamic and neurohormonal imbalance after myocardial infarction. Experimental studies and clinical trials suggest that cellular cardiomyoplasty with stem/ progenitor cells may improve cardiac function and prevent ventricular remodeling of the injured heart. Although the mechanisms are still in intensive debate, cellular cardiomyoplasty with stem cells has already been introduced into the clinical settings. However, it is an important challenge how donor cells are delivered to the targeted area. In early studies in animals, intramyocardial injection of stem cells after thoracotomy is the main transplantation route which is not suitable to most patients in clinical settings. Then the catheter-based infusion of stem cells is clinically introduced and rapidly developed because of its safety, convenience and micro-invasion. We hypothesize that catheter-based transplantation with stem cells may be a promising means to treat ischemic heart diseases in the future in clinical settings. c 2007 Elsevier Ltd. All rights reserved.
Introduction and hypothesis Myocardial infarction (MI) is the leading cause of congestive heart failure (CHF) and death in the
* Corresponding author. Tel.: +86 10 64456200. E-mail address: [email protected] (Z.-Z. Li).
industrialized world [1]. Although there have been great advances in cardiovascular therapeutics, treatment of ischemic heart diseases (IHD) remains an important challenge. Current therapeutic means focus on ameliorating the progression of ventricular remodeling and subsequent heart failure, but incapable of regenerating the lost cardiomyocytes caused by necrosis and apoptosis. Recent evidence
0306-9877/$ - see front matter c 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.mehy.2007.04.013
Trans-coronary transplantation may be an optimal route in cellular cardiomyoplasty with stem cells
has been presented that human myocardium can reenter the cell-cycle and divide after acute myocardial infarction (AMI), but this intrinsic repair capacity is too weak to substantially regenerate infarcted cardiomyocytes [2,3]. Therefore, it is necessary to develop a new method to promote myocardium regeneration. The discovery of plasticity of adult stem cell may bring about a breakthrough in treatment of MI. Stem cells are capable of self-renewal and differentiation to specialized progeny. Traditional standpoint is that tissue-resident adult stem cells only can differentiate into special kind of progeny. Plasticity indicates that stem cells can transdifferentiate into other cell types outside their original tissues under certain conditions [4–6]. Based on the advances in stem cell research, there has been a new method in cardiovascular therapeutics in recent years, named as cellular cardiomyoplasty (CCM), which is an outside intervention to support the reparative process in the heart through transplantation of stem/progenitor cells or cardiac cells, or mobilizing peripheral blood- or bone marrow-derived stem cells into the site of cardiac injury. CCM with stem cells is a possible option to reverse the deleterious hemodynamic and neurohormonal effects after MI; various preclinical animal studies show the potential of stem cells to regenerate myocardium, improve perfusion of the infarcted area and improve cardiac function [7–9]. Early phase I clinical studies indicate that transplantation of stem cells is feasible and may have beneficial effects on ventricular remodeling after MI [10–15]. Although several studies indicated that bone marrow-derived stem cells did not have the potential to transdifferentiate into cardiomyocytes in vitro and in vivo [16,17], most of other experimental studies suggested that implanted stem cells could transdifferentiate into cardiomyocytes, vascular smooth muscle cells and endothelial cells, decrease apoptosis of hypertrophied myocytes in the peri-infarction region, decrease size of fibrosis scar, enhance myocardial blood flow so as to improve perfusion, rescue hibernating myocardium, excrete cytokines or growth factors causing proliferation of endogenous cardiac myocytes and enhance resident cardiac stem cell function [18–23]. However, it is an important challenge how donor cells are delivered to the targeted area. In early studies in animals, intramyocardial injection of stem cells after thoracotomy is the predominant transplantation route which is not suited to most patients in clinical settings. Then the catheterbased infusion of stem cells is clinically introduced and rapidly developed because of its safety, conve-
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nience and micro-invasion. We hypothesize that catheter-based transplantation with stem cells may be a promising means to treat ischemic heart diseases in the future in clinical settings.
Intracoronary infusion of stem cells Feasibility The main objective of various cell delivery approaches is to implant sufficient numbers of cells into the target area of myocardium and to keep maximum retention of cells within that area. Previous animal experiments and clinical studies demonstrated that several delivery routes of stem cells, including intramyocardial injection after thoracotomy, percutaneous catheter-based injection (intramyocardial injection and intravascular injection) and trans-peripheral-vascular route, were effective and safe. Among others, catheter-based transplantation of stem cells was especially the focus of interest. Since Strauer et al. [24] for the first time successfully transplanted bone marrow-derived mononuclear cells to treat patients with AMI by transcoronary infusion in 2002, studies by intracoronary infusion have been rising in animal experiments and clinical studies. Most of these studies demonstrated that intracoronary infusion of various stem cells was safe and effective to IHD. In these studies, cells were delivered through the over-the-wire balloon catheter during transient balloon inflations to maximize the contact time of the cells with the vascular walls of the infarct-related area. Intracoronary infusion is quite easy to perform in several minutes because of its familiarity by clinical cardiologists, which is advantageous over intravenous infusion because it can deliver the relatively more cells to the target area during the balloon inflations. Infusion in the infarct-related artery allows the stem cells to transmigrate the vascular walls into the peri-infarct zone, which differ from intramyocardial injection that may lead to disperse islands of cells in the infarct-related zone, providing a substrate for arrhythmias. Intracoronary infusion of stem cells is especially suited for the local microenvironment in which some beneficial cytokines are highly expressed, severely inflammatory reactions subside to avoid killing implanted cells, and fibrous scar is not yet formed that may lead to the disconnection between implanted cells and host cardiomyocytes. However, the percentage of infused cells by intracoronary delivery migrating into the targeted area is not clear. In 2005, Hofmann et al. [25] for
1214 the first time clinically transplanted unselected bone marrow cells (BMCs) and CD34+ cells labeled with 18F-fluoro-deoxy-glucose (18F-FDG) by intracoronary delivery. Positron emission tomography imaging showed that 1.3–2.6% of BMCs were detected in the infarcted myocardium; the remaining activity was found primarily in liver and spleen. Regarding CD34+ cells, 14–39% of the total radioactivity was detected in the infarcted myocardium. This study demonstrated that the donor cells which were transplanted by intracoronary infusion did actually engraft into the post-infarction myocardium to restore the injured heart. In addition, recent study reported by Qian et al. [26] demonstrated that 6.8 ± 1.8% of bone marrowmononuclear cells radiolabeled by 18F-FDG engrafted into the post-infarction myocardium at 1 h after being intracoronarily delivered, and the retention rate of labeled cells in the myocardium was positively correlated with the size of underperfused area.
Safety It is the most important issue whether intracoronary infusion of stem cells is safe. Up to date, most of the animal experiments and clinical trials have demonstrated that intracoronary transplantation of stem cells is safe. However, there still have been the following studies indicating that several unexpected situations were possibly complicated with this transcatheter procedure. First, Vulliet et al. [27] showed that intracoronary infusion of bone marrow-derived mesenchymal stem cells (MSCs) caused microinfarction in healthy dogs, which for the first time raised caution to the safety of intracoronary infusion. Second, Van derheyden et al. [28] found that intracoronary infusion stem cells accelerated atherogenesis progress in an AMI patient. However, this is a single case report which is not representative. Third, Kang et al. [29] showed granulocyte-colony stimulating factor (G-CSF) administration associated with intracoronary infusion of circulating stem cells improved cardiac function, and promoted angiogenesis in patients with MI. However, an unexpectedly high rate of in-stent restenosis (ISR) at culprit lesion in patients who received G-CSF was observed. In addition, Steinwender et al. [30] sought to evaluate a clinical and angiographic long-term safety profile of G-CSF application combined with transcoronary transplantation of peripheral blood stem cells (PBSC) after recent stent implantation for AMI.
Li et al. After 6 months, in the 20 patients who received PBSCs transplantation, mean left ventricular ejection fraction (LVEF) improved from 46.4 ± 8.1% at baseline to 54.3 ± 11% (P < 0.001). Control coronary angiography revealed a significant in-stent restenosis of the infarct-related coronary artery, defined as >50% stenosis, in eight patients (40%), which was complicated by reinfarction in two patients (10%). These findings indicated that transcoronary transplantation of G-CSF-mobilized PBSCs favorably influences cardiac function and can be performed without adverse periprocedural events. However, significant in-stent restenosis and reinfarction seem to occur frequently during the following 6 months. Similarly, Inoue et al. [31] also found that in 40 patients undergoing coronary stenting, after baremetal stenting, circulating CD34-positive cells increased, reaching a maximum on day 7 after stenting. Cell culture assay on day 7 showed that mononuclear cells differentiated into endothelium-like cells after bare-metal stenting. In patients with restenosis, mononuclear cells differentiating into smooth muscle-like cells also were observed. These results indicated that stent implantation may induce differentiation of bone marrow cells into endothelial or smooth muscle cells. Endothelial cells may participate in re-endothelialization, a protective reaction against vascular injury, whereas smooth muscle cells may participate in neointimal thickening and restenosis. Regarding the possible increase in in-stent restenosis following stem cell infusion, there are three reasons to interpret: (1) improper procedure during the infusion because of the balloon inflation possibly result in more significant stimulations to the damaged vessel wall; (2) mononuclear cells contain several types of stem cells as well as pro-inflammatory cells which may adhere to the stent-implanting segment of vascular wall; (3) several chemotatic factors, such as G-CSF, can attract circulating inflammatory cells engrafting into the stent-implanting vessel wall, which then trigger inflammatory reaction; (4) the inflammatory response after vascular injury triggers the mobilization of smooth muscle progenitor cells from bone marrow to differentitate into smooth muscle cells accumulating in the neo-intima. Even though above findings do exist, other similar investigations did not find the similar results. Moreover, most of current studies on animals and patients have not found other adverse events complicated with intracoronary infusion of stem cells, such as tumorigenesis, arrhythmias and functional exacerbation.
Trans-coronary transplantation may be an optimal route in cellular cardiomyoplasty with stem cells
Effectiveness Another important issue involved in intracoronary infusion of stem cells is whether it is effective on post-infarction or other injured hearts. Over the last 5 years, several clinical studies published have used autologous bone marrow as well as peripheral blood-derived progenitor cells, which were transplanted via intracoronary infusion to the ischemic area. The initial results demonstrated the safety and benefit of this strategy, which appears to be relatively inexpensive and free of side effects. Up to today, several clinical trials have already demonstrated that intracoronary infusions of adult stem or progenitor cells are effective on patients with AMI, old MI, ischemic cardiomyopathy and heart failure, including improvement in LVEF, inhibition of ventricular remodeling, decrease of infarcted area and cardiac apoptosis, inhibition of inflammatory response, prevention of cardiac fibrosis, promotion of angiogenesis, and secreting cytokines by paracrine mechanism, etc. [7–15]. In addition, Katritsis et al. [32] found that intracoronary transplantation of MSCs and endothelial progenitor cells (EPCs) did not appear to be arrhythmogenic, even mitigated the bout of ventricular arrhythmias, in five patients with a history of previous anteroseptal MI and ICD implant for ventricular arrhythmias underwent. Schueller et al. [33] found that intracoronary infusion of bone marrow cells beneficially increased heart rate variability in patients with transmural MI after three to twelve months of follow up. These findings further extended the practical applications for intracoronary infusion of stem cells in clinical settings.
Donor cell types Up to date, there have been many types of stem cells used to treat cardiovascular diseases by transcoronary infusion, including bone marrow- or peripheral blood-derived mononuclear cells [34,35], AC133+ cells [36] and CD34+ cells [37], bone marrow-derived MSCs [38], unfractionated BMCs [39], EPCs [40]. Previous studies related to CCM with stem cells are involved in almost all of IHD, such as AMI [41], ischemic cardiomyopathy [42], chronic total obstruction of coronary artery [35] and OMI [43].
Timing window of transplantation It is an important involvement when intracoronary infusion of stem cells is most effective, which ex-
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erts remarkable impacts on engraftment, survival and bioactivities of implanted cells in vivo. However, there have been the least studies to investigate that. Currently, there are several different standpoints about the optimal timing window of transplantation: (1) Early infusion, which means that intracoronary infusion is performed from immediate AMI to 1-week post-infarction. Theoretically, the inflammatory reactions are so intense during this period that the microenvironments in the post-infarction myocardium are unsuitable for implanted cells to survive and exert their bioactivities in vivo. Li et al. [44] reported that 2 weeks after AMI is the optimal timing for transplantation, which was better than immediate and 4-week post-AMI. The study reported by Janssens et al. [45] and REPAIR trial [46] indicated that transplantation of stem cells during 24 h after AMI had no functional benefits. In contrast, Ge et al. [47] for the first time demonstrated that early intracoronary infusion of bone marrow-mononuclear cells in patients within 24 h after AMI resulted in a significant increase in LVEF and prevented left ventricular dilation at 6-month follow-up. (2) Intermediate-stage transplantation, which means the period from 1-week post-infarction to not shaping of fibrotic scar. During this period, inflammatory reactions gradually subside and infarct-scar is not formed yet, therefore, the implanted cells can survive and act better. Currently, most of the clinical trials have been performed within this period. (3) Delayed transplantation, indicating that fibrotic scar has already formed in infarcted region. During this period, infarcted region is not suitable for the implanted cells to survive and limits the connections between donor cells and host myocardium, thus supplying a substrate of arrhythmias. However, IACT trial [43] indicated that intracoronary infusion of stem cells in patients with OMI caused a reduction by 30% in MI area, an increase by 57% in ventricular wall motion velocity in infarcted region and by 15% in LVEF, accompanied by improvement in exercise tolerance at 3-month follow-up. This study first demonstrated that intracoronary transplantation of stem cells during later-stage was still effective, thus extending the objects that are suitable to receive stem cells transplantation. Because of the differences in situations of included patients, follow-up, donor cell type, design of trials, etc., the results from above studies are different. Moreover, the milieu in the infarctedmyocardium is different in different situations of diseases and complicated diseases; therefore, the best timing window of transplantation should be individualized in single patient.
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Indications for intracoronary infusion of stem cells A portion of patients with AMI and ischemic cardiomyopathy had a great deal of stunning or hibernating myocardium which will restore their functions after successful revascularization. Subsequently, there will be significant improvements in cardiac function of these patients. Therefore, stem cell transplantation is not remarkably beneficial to these patients. Regarding those patients with AMI and ischemic cardiomyopathy whose cardiac function are still seriously damaged after revascularization, stem cell infusion is suitable. Furthermore, the more damage in cardiac function, the more effective is cell transplantation [14,48,49]. In addition, CHF complicated with dilated cardiomyopathy (DCM) is also the indications for stem cells transplantation. However, it is uncertain which situation of CHF is suitable to receive cell therapy. Agbulut et al. [50] for the first time demonstrated that intramyocardial injection of bone marrow-mononuclear cells was effective on mice with adriamycin-induced DCM. Their study suggested that stem cell transplantation is promising in the treatment of drug-induced cardiomyopathy or CHF.
Problems and perspective Intracoronary infusion of stem cells has been proven to be safe and effective to treat ischemic heart diseases in numerous animal experiments and clinical studies in recent years. However, there are still many problems to be resolved in the future study such as the following: (1) Does the plasticity really exist? And if it is true, what’s the molecular mechanism? (2) Which type, how many and which transplantation route of donor cells is the best? (3) What is the fate of donor cells in the post-infarction myocardium during long-term investigation? (4) How long does the short-term effectiveness originated from donor cells remain? (5) How does the dynamic distribution of intracoronarily delivered donor cells change in vivo? Notwithstanding, the mechanisms of CCM with stem cells are poorly understood, the exact homing mechanism and organ-specific differentiation signals for stem cells are not clearly understood, and fusion of transplanted stem cells with resident cardiomyocytes may be an alternative explanation for previous claims of transdifferentiation; it is interesting that cell therapy is already being introduced into the clinical settings. So far, most of the
Li et al. clinical studies related to CCM are small and uncontrolled. These studies have applied different tissue-derived cells to a small number of patients with different situations of IHD. Although these preclinical data indicate that CCM may be effective, we should carefully read these data. In the future, researches about CCM need to be largesample, long-term, double-blind, randomized-controlled clinical trials to reveal the actual effects of stem cell therapy in the real clinical application.
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