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J Am Coll Cardiol, 2007; 49:1137-1148, doi:10.1016/j.jacc.2006.10.072 (Published online 5 March 2007).
© 2007 by the American College of Cardiology Foundation
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STATE-OF-THE-ART PAPER

Role of Imaging in Cardiac Stem Cell Therapy

Saskia L.M.A. Beeres, MD*, Frank M. Bengel, MD{dagger}, Jozef Bartunek, MD{ddagger},a, Douwe E. Atsma, MD*, Jonathan M. Hill, MD§, Marc Vanderheyden, MD{ddagger},a, Martin Penicka, MD||, Martin J. Schalij, MD*, William Wijns, MD{ddagger},a and Jeroen J. Bax, MD*,*

* Department of Cardiology, Leiden University Medical Center, Leiden, the Netherlands
{dagger} Division of Nuclear Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland
{ddagger} Cardiovascular Center Aalst, Aalst, Belgium
§ Department of Cardiovascular Diseases, King’s College, London, United Kingdom
|| CardioCenter, 3rd Medical School, Charles University and University Hospital, Prague, Czech Republic.

Manuscript received August 28, 2006; revised manuscript received October 11, 2006, accepted October 23, 2006.

* Reprint requests and correspondence: Dr. Jeroen J. Bax, Department of Cardiology, C5-P, Leiden University Medical Center, P.O. Box 9600, 2300RC Leiden, the Netherlands. (Email: jbax{at}knoware.nl).


   Abstract
Top
 Abstract
Cell Tracking by Use...
 Imaging to Evalute Functional...
 Conclusions
 References
 
Stem cell therapy has emerged as a potential therapeutic option for cell death-related heart diseases. Preclinical and a number of early phase human studies suggested that cell therapy may augment perfusion and increase myocardial contractility. The rapid translation into clinical trials has left many issues unresolved, and emphasizes the need for specific techniques to visualize the mechanisms involved. Furthermore, the clinical efficacy of cell therapy remains to be proven. Imaging allows for in vivo tracking of cells and can provide a better understanding in the evaluation of the functional effects of cell-based therapies. In this review, a summary of the most promising imaging techniques for cell tracking is provided. Among these are direct labeling of cells with super-paramagnetic agents, radionuclides, and the use of reporter genes for imaging of transplanted cells. In addition, a comprehensive summary is provided of the currently available studies investigating a cell therapy-related effect on left ventricular function, myocardial perfusion, scar tissue, and myocardial viability.

Abbreviations and Acronyms
  CT = computed tomography
  FDG = fluorodeoxyglucose
  HMPAO = exametazime
  LV = left ventricle/ventricular
  LVEDV = left ventricular end-diastolic volume
  LVEF = left ventricular ejection fraction
  MRI = magnetic resonance imaging
  PET = positron emission tomography
  SPECT = single-photon emission computed tomography

Stem cell transplantation is being widely investigated as a potential therapy for cell death-related heart diseases (1). Several cell types, including embryonic stem cells (2), skeletal myoblasts (3,4), bone marrow-derived cells (5–7), or cardiac resident stem cells (8,9), are being tested, and preclinical studies have shown the potential of various approaches to repair acutely or chronically damaged myocardium.

In some experimental settings, transplantation of stem or progenitor cells after myocardial infarction reduces scar formation and fibrosis, and preserves cardiac function. Moreover, different subsets of progenitor cells were shown to augment perfusion. Both observations may be related to a direct physical effect (differentiation of progenitor cells to endothelial cells, smooth muscle cells, and cardiomyocytes) and/or to the release of paracrine factors by progenitor cells, which prevent apoptosis of cardiomyocytes, modulate scar development, or promote angiogenesis (1).

On the basis of these encouraging preclinical studies, there is a growing number of early phase human studies that aim to demonstrate the feasibility and potential efficacy of cell-based therapies in the clinical setting (10–35). This rapid translation into clinical studies has left a lot of questions concerning cell therapy unanswered. For example, the optimal cell type, the number of cells to be delivered, the most suitable route for cell delivery, and the optimal time point for cell delivery after myocardial infarction are unknown. Furthermore, the biodistribution of the therapeutic cells after delivery and the specific mechanism by which therapeutic cells contribute to functional improvement remain to be investigated. Imaging is crucial for in vivo tracking of cells and better understanding and evaluation of the effects of cell therapy. In this review, we have attempted to summarize the available evidence on imaging of cell therapy.


   Cell Tracking by Use of Noninvasive Imaging
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 Cell Tracking by Use...
Imaging to Evalute Functional...
 Conclusions
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The ideal imaging modality should provide integrated information related to the entire process of cell engraftment, survival, and functional outcome. Clinically established parameters of noninvasive imaging, such as contractile function, perfusion, and viability of the myocardium, do not provide direct visualization of transplanted cells, their biology or function. Thus, a number of contrast agents and detectors for noninvasive, repeatable visualization of therapeutic cells in vivo have been pursued (36). Such imaging approaches may not only refine the understanding of therapeutic mechanisms in preclinical studies but may also have direct clinical applications. Most of the available cellular molecular imaging techniques are also applicable in humans, and therefore may facilitate rapid translation of cell-based therapies into clinical practice. Table 1 and Figure 1 summarize labeling strategies for in vivo surveillance and tracking of various cell populations.


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  		Table 1 Techniques for In Vivo Imaging of Labeled Transplanted Cells
 

Figure 1
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  		Figure 1 Approaches for Cell Tracking by Noninvasive Imaging

Cells are labeled directly for magnetic resonance imaging (MRI), positron emission tomography (PET), single-photon emission computed tomography (SPECT), or with a reporter gene for subsequent reporter-gene imaging using either of the techniques. F18-FDG = fluorodeoxyglucose; HMPAO = exametazime; IFP = iron fluorescent particle; SPIO = super-paramagnetic iron oxide; Tc = technetium.

 
Radionuclide technology and magnetic resonance imaging (MRI) are best suited to meet such broad objective thanks to their resolution and clinical applicability, with MRI having some advantages in terms of spatial resolution (Table 2). Cells can be labeled directly with super-paramagnetic iron oxide agents or radionuclides before their application for subsequent in vivo visualization of their distribution. Additionally, genetic labeling with reporter genes that can be traced with imaging probes has been introduced, which will allow for repeatable tracking of cellular and subcellular function over a longer period of time. The use of non-invasive imaging modalities in preclinical cell therapy studies revealed key aspects of cell biology that will not be observed by other approaches except for histologic analysis. In particular, the ability to dynamically follow cell trafficking and survival over longer periods of time contributed to the understanding of the potential mechanism of benefit.


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  		Table 2 Nuclear Imaging and MRI in Cardiac Stem Cell Therapy
 
Direct labeling of cells using magnetic resonance agents.   Magnetic resonance imaging has become a key surrogate end point to demonstrate efficacy in early phase, small-sized studies (37). Magnetic resonance imaging can provide detailed morphologic and functional information and, therefore, seems ideally suited to integrate efficacy assessments with the capability for cell tracking. The potential for assessing engraftment of therapeutic cells was quickly realized, and investigations are now focusing on refining contrast agents to ensure maximum signal for minimum labeling. Initial animal model studies using micron scale particles (38,39) or nanoparticles of iron oxide (40,41) showed the potential for non-toxic labeling of hematopoietic bone marrow-derived and mesenchymal stem cell populations without affecting their transdifferentiation capacity. In the cardiovascular setting, this cell labeling technology was coupled with direct delivery methods using endomyocardial injections, demonstrating that transplanted cells could be imaged shortly after delivery with a high degree of spatial resolution using MRI (40) (Fig. 2). Iron oxide labeling can also be used to track smaller numbers of cells in homing experiments allowing for in vivo identification of mesenchymal stem cells that migrated to infarcted myocardium after intravenous administration (41). Yet, in the studies described in the preceding text, the lowest detectable number of cells was 105 with the use of conventional MRI scanners without any sequence modification. This threshold of detection can be lowered using high-field magnets (11.7-T) such that single cells containing a single iron particle can be detected and tracked (42).


Figure 2
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  		Figure 2 Magnetic Resonance Imaging Labeling Using Combined Modality Imaging Agent

Fluorescent green component of iron-fluorophore-labeled porcine mesenchymal stem cells delivered by intramyocardial injection with nuclei stained blue (left). Same panel imaged using Nomarski optics (middle). Hemotoxylin/eosin stain of same panel with iron-labeled cells appearing brown (right). Magnetic resonance imaging long-axis slice of a porcine left ventricle after anteroapical intramyocardial injection of iron-fluorophore-labeled mesenchymal stem cells (bottom). The black area on the endomyocardial border (arrows) is the signal void created by the iron-labeled cells.

 
There are potential theoretical disadvantages to the use of magnetic labeling. Most importantly, the imaging signal is not directly linked with cell viability. There is a risk for release of iron oxide after cell death and its accumulation in bystander cells confounding any quantitative assessment of cell trafficking. In addition, cell division can dilute the magnetic label within only a few cell divisions. Novel direct labeling techniques like Clio-tat peptides (43) or magnetic relaxation switches (44) are under development in preclinical studies and could help overcome some of these limitations in the future. Despite minimal effect of iron oxide particles on in vitro proliferative capacity and cell viability (38), there are recent data raising concern about the impact on the differentiation capacity of mesenchymal stem cells along a chondrogenic differentiation pathway (45). On the other hand, this effect may be compound specific, because the 2 Food and Drug Administration-approved iron oxide-based agents affect neither hematopoietic nor mesenchymal stem cell function or differentiation capacity (46). Before clinical application, future work is required to investigate the effect of iron-labeling on stem cell proliferation and differentiation.

Direct labeling of cells using radionuclides.   Direct labeling of cells with radionuclides provides the advantage of a lower background signal as compared with MRI. However, higher sensitivity is achieved at the cost of lower spatial resolution. Various clinically applicable radionuclides have been used, based on previously established protocols for leukocyte or thrombocyte scintigraphy. Direct labeling with radionuclides appears highly informative for clinical studies addressing homing and biodistribution after cell injection. Indium (In)-111–labeled endothelial and hematopoietic progenitor cells were found to accumulate in infarcted rat myocardium after intraventricular injection (Fig. 3), but the overall radioactivity in the heart was only around 4.7% of the injected dose (47). These data suggest that only a small number of cells ultimately home to injured myocardium, but they also corroborate the high sensitivity of the nuclear imaging technique. In another study using In-111–labeled mesenchymal stem cells in pigs, accumulation in the lungs was observed early after intravenous injection, which was found to obscure assessment of myocardial cell trafficking (48). This observation was confirmed in rats by another group, using technetium (Tc)-99m exametazime (HMPAO) for labeling of bone marrow-derived mesenchymal stem cells and observing entrapment of the donor cells in the lungs (49). More recently, homing of In-111–labeled mesenchymal stem cells to infarcted myocardium was successfully visualized in a dog model using single-photon emission computed tomography (SPECT)-CT (41). Finally, the positron emission tomography (PET) tracer F18-fluorodeoxyglucose (F18-FDG) has been used for labeling and imaging of bone marrow cells in humans. Myocardial accumulation of cells was demonstrated after intracoronary infusion, but not after intravenous delivery. With immunomagnetically enriched CD34-positive cells, 14% to 39% of total injected radioactivity was detected in infarcted myocardium after intracoronary injections, preferentially in the border zone (50). Other data indicate that radiolabeling could be used to assess early kinetics after cell injection. Tc-99m-HMPAO–labeling of mononuclear cells indicated that cardiac engraftment of cells is a dynamic process: the radioactivity uptake by the heart was 5% at 2 h and 1% at 18 h after transcoronary cell transplantation in a patient with acute myocardial infarction (51). These data support the translational potential of nuclear imaging to guide cell therapy approaches from preclinical to clinical applications and to provide mechanistic information in applications like intracoronary administration with higher sensitivity than MRI. Future work should aim to prolong the half-life time of radioisotopes in order to prevent loss of the imaging signal within a few days.


Figure 3
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  		Figure 3 Tracking of In-111–Labeled Endothelial Progenitor Cells in the Rat Heart

After experimental myocardial infarction, 106 indium (In)-111–labeled cells were injected intramyocardially (left) or intravenously (right). Shown are planar scintigraphic images of the whole animal, along with magnification of the cardiac area. Significant cardiac retention of cells in the heart is only identified after intramyocardial injection (arrow).

 
Reporter genes for cardiovascular cell imaging.   The usefulness of reporter genes for imaging of gene transfer to the myocardium has been established recently (52). This principle may be expanded to imaging of cell-based therapies. A reporter gene of choice can be transferred to cells for genetic labeling, before their in vivo administration. After application, cells can then be detected by an intravenously administered, radio-labeled or optical reporter probe, which is specific for the reporter gene and which accumulates solely in the transduced therapeutic cells (Fig. 4). Because accumulation of the reporter probe requires expression of the reporter gene and activity of the reporter-gene product, the imaging signal will be dependent on viability of the therapeutic cells. This is in contrast with direct "passive" labeling techniques and provides a more specific readout. Additionally, imaging can be performed repeatedly and is not limited by radioactive decay of the initial label load. Observation of genetically labeled cells is thus possible over a long period of time, and may only be limited by epigenetic silencing (53).


Figure 4
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  		Figure 4 Tracking of Genetically Labeled Progenitor Cells by Positron Emission Tomography

3 x 106 endothelial progenitor cells transfected with the sodiumiodide symporter gene were injected intramyocardially in a healthy rat. After injection of N-13 ammonia, homogeneous myocardial perfusion is shown in grayscale on the top. Perfusion images are overlayed with images of reporter-gene expression (bottom). obtained after injection of I-124 sodiumiodide (red/yellow). Regional accumulation of the reporter probe depicts presence of viable transplanted cells at the injection site in the lateral wall. LA = left atrium; LV = left ventricle; RA = right atrium; RV = right ventricle.

 
Proof of principle for imaging of genetically labeled cells was obtained using rat cardiomyoblasts, which were infected ex vivo with adenovirus carrying the HSV1-sr39tk and luciferase reporter genes. Cell-specific in vivo optical and micro-PET imaging was feasible for up to 2 weeks after direct injection of cells into the myocardium of nude rats. For optical imaging, 5 x 105 cells were detectable, while PET images were obtained using 3 x 106 cells (54). Subsequent preclinical studies used reporter-gene labeling to demonstrate usefulness of novel intramyocardial injection techniques and assess cell survival, proliferation, and migration over a longer period of time (55,56).

Importantly, genetic labeling also holds promise to provide insights into subcellular mechanisms that take place within therapeutic cells. Reporter genes may be expressed under control of restrictive promoters that are sensitive to certain endogenous molecules. Despite bearing a conceptual promise, the use of reporter-gene imaging to monitor cell transplantation is still limited to animal model studies. In order to proceed from bench to bedside, further work is required to develop nonimmunogenic probes, improve transfection stability, and reduce the interference of transfection with the cell function and desired molecular effect. Strength of the imaging signal is critical, and additional work is necessary to establish a robust approach for cell visualization that is also practical for use in the clinical setting.


   Imaging to Evalute Functional Effects of Cell Therapy
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 Abstract
 Cell Tracking by Use...
 Imaging to Evalute Functional...
Conclusions
 References
 
Imaging may be particularly helpful in evaluating the functional effects of cell therapy. The various clinical studies have mainly focused on detection of differences in left ventricular (LV) function, myocardial perfusion, infarct size, and myocardial viability.

LV function.   Table 3 summarizes the 17 available studies (including 10 or more patients) that have evaluated changes in LV function after cell therapy. In total, 526 patients underwent cell therapy in these studies. Ten studies were performed in the setting of acute myocardial infarction, and 7 studies were performed in the setting of chronic ischemic heart disease. Assessment of function was performed ranging from 3 to 18 months after cell therapy.


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  		Table 3 Effect of Cell Therapy on LV Function and Volumes
 
Ten studies showed an improvement in LV ejection fraction (LVEF), indicating improved systolic function. The majority of studies indicated small improvements in LVEF (range 2.9% to 9.3%), but Chen et al. (19) demonstrated in 34 patients with acute myocardial infarction an improvement of 18%. Different techniques were used to assess LV function and volumes, including LV angiography, 2-dimensional echocardiography, gated SPECT, radionuclide ventriculography, and MRI. The most accurate assessment of LVEF and LV volumes is MRI, and Fernández-Avilés et al. (18) demonstrated an increase of 5.8% in LVEF as assessed by MRI, whereas no improvement was seen in control patients. The global improvement of LVEF was mainly related to an improvement of regional LV function in the infarct zone, although improvement of function in the infarction border zone has also been reported.

Left ventricular end-diastolic volume (LVEDV) remained unchanged in most (12 of 17) studies, indicating absence of LV reverse remodeling. However, since LVEDV did not increase either, one could argue that cell therapy prevented progressive LV dilatation. In support of this, Bartunek et al. (20) demonstrated that the LVEDV index remained unchanged in patients undergoing cell therapy, whereas an increase from 91 ± 7 ml/m2 to 103 ± 9 ml/m2 (p < 0.05) was observed in control patients.

The improvement of LVEF may be a time-dependent process; in the BOOST (BOne marrOw transfer to enhance ST-segment elevation infarct regeneration) trial, sequential measurements were performed in 30 bone marrow cell transfer patients and in 30 control patients, at 6 and 18 months. At 6 months, MRI demonstrated an increase in LVEF of 6.7% in bone marrow cell transfer patients, as compared with 0.7% in control subjects (p < 0.01). However, at 18 months, the LVEF change was not significantly different between the 2 groups (+5.9% vs. +3.1%; p = NS). Analysis of the time course of LVEF improvement, however, revealed a significantly faster recovery of LVEF in the bone marrow cell transfer patients than in control patients (p < 0.01) (17).

Myocardial perfusion.   A total of 11 studies (including 239 patients) evaluated the effect of cell therapy on perfusion (Table 4). Five studies were performed in the setting of acute myocardial infarction, 3 studies in patients with chronic infarction, and 3 studies in patients with stress-induced ischemia. Assessment of perfusion was performed ranging from 3 to 12 months after therapy. The clinically available tools for assessment of myocardial perfusion include nuclear imaging with PET or SPECT, MRI using first-pass perfusion, or myocardial contrast echocardiography. In addition, coronary blood flow can invasively be assessed using the Doppler flow wire at rest and during pharmacologic stress. Subsequent calculation of the coronary flow reserve provides insight into the integrity of both the epicardial conduit arteries and the distal microvascular bed.


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  		Table 4 Effect of Cell Therapy on Myocardial Perfusion
 
In 9 of 11 currently available studies, SPECT was used, and only Janssens et al. (21) used PET to evaluate the effect of cell therapy on perfusion. It should be emphasized, however, that only PET permits absolute quantification of myocardial perfusion, whereas SPECT provides information on relative changes in tracer uptake.

The majority (10 of 11) of studies demonstrated some effect of cell therapy on perfusion. For example, Bartunek et al. (20), using resting Tc-99m sestamibi SPECT, demonstrated a decrease in resting perfusion defect size at 4 months. Conversely, defect size did not change in control patients. Similar results were reported by other groups. Of note, the only study with PET could not demonstrate an increase in perfusion (21).

The majority of the studies evaluated only resting perfusion, but few studies evaluated both rest and stress perfusion with SPECT. Beeres et al. (31) demonstrated in patients with refractory angina a significant decrease in the number of segments with stress-inducible ischemia. A patient example with a reduction in ischemia is shown in Figure 5. Perin et al. (33) presented similar results with stress-rest Tc-99m sestamibi SPECT in heart failure patients.


Figure 5
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  		Figure 5 Technetium-99m Tetrofosmin SPECT Polar Maps at Baseline and 3 and 12 Months After Cell Therapy

Technetium-99m tetrofosmin single-photon emission computed tomography polar maps of a patient with stress-induced ischemia in the inferolateral myocardium at baseline (left). Three months after intramyocardial injection of autologous bone-marrow-derived mononuclear cells there is a reduction in the extent of stress-induced ischemia (middle). The effect is sustained at 12 months follow-up (right). Reprinted from Beeres et al. (31), with permission.

 
Three studies used intracoronary Doppler with 2 of 3 studies showing an improvement in coronary flow reserve. For example, a substudy of the TOPCARE-AMI (Transplantation of Progenitor Cells and Regeneration Enhancement in Acute Myocardial Infarction) trial revealed that progenitor cell therapy was associated with complete restoration of coronary flow reserve due to a substantial improvement of maximal coronary vascular conductance capacity (15).

Infarct size.   In the clinical setting, 12 studies (including 355 patients) evaluated the effect of cell therapy on infarct size (Table 5). Seven studies were performed in the setting of acute infarction, whereas 5 were performed in patients with chronic infarction. Assessment of scar tissue was performed ranging from 3 to 18 months after therapy. A variety of techniques is available to assess infarct size, including techniques that directly visualize the scar tissue (i.e., nuclear imaging with PET or SPECT, contrast-enhanced MRI, myocardial contrast echocardiography), or indirect approaches that visualize the extent and severity of LV dysfunction (LV angiography, 2-dimensional echocardiography, or cine MRI). Eight studies evaluated infarct size with SPECT or contrast-enhanced MRI, whereas 4 studies evaluated systolic dysfunction in the infarct zone as an indicator of extent of scar tissue. Seven of 12 studies demonstrated some reduction in infarct size, both in the setting of acute and chronic infarction.


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  		Table 5 Effect of Cell Therapy on Infarct Size
 
The most accurate technique is contrast-enhanced MRI, allowing precise detection of scar tissue and currently the only technique discriminating between subendocardial and transmural infarction (57). In the BOOST trial, contrast-enhanced MRI was performed at baseline, at 6 and 18 months follow-up. At 18 months, a mean reduction in infarct size of 13 ± 12 ml was demonstrated in patients undergoing cell therapy, but control patients exhibited a comparable reduction in infarct size (10 ± 13 ml; p = NS vs. patients undergoing cell therapy) (17). Of note, Ingkanisorn et al. (58) recently demonstrated a significant reduction in infarct size on contrast-enhanced MRI performed at 1.7 ± 0.8 days and 2 months after acute myocardial infarction. Clearly, randomized controlled trials are needed to evaluate changes in infarct size after cell therapy as compared with the natural evolution after reperfused acute infarction.

Myocardial viability.   A total of 10 studies (in 243 patients) evaluated changes in viability after cell therapy (Table 6). Six studies were performed in the setting of acute infarction, 2 studies after chronic infarction, and 2 studies in patients with stress-induced ischemia. Follow-up ranged from 3 to 6 months after cell therapy.


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  		Table 6 Effect of Cell Therapy on Myocardial Viability
 
The clinically available techniques for evaluation of viability include nuclear imaging with PET (mainly using F18-FDG, evaluating glucose utilization) or SPECT (with F18-FDG or Tc-99m–labeled agents), or low-dose dobutamine echocardiography (assessing contractile reserve). Contractile reserve can also be assessed by low-dose dobutamine MRI. Non-fluoroscopic catheter-based electromechanical mapping enables identification and localization of viable myocardial tissue by simultaneous assessment of electrical activation and local mechanical response.

Five studies used F18-FDG PET or SPECT to evaluate viability in the infarct zone of which 4 reported an increased F18-FDG uptake after cell therapy. For example, in the IACT (Regeneration of Human Infarcted Heart Muscle by Intracoronary Autologous Bone Marrow Cell Transplantation in Chronic Coronary Artery Disease) study, a mean increase of 15% in F18-FDG uptake in the infarct zone was demonstrated (25). Similarly, in the TOPCARE-AMI study, mean F18-FDG uptake in the infarct zone increased from 55% to 58% at 4 months; however, data on control patients were not available (14).

Three studies used low-dose dobutamine echocardiography with 2 of 3 studies showing no improvement in contractile reserve, in contrast with the improvement observed in viability studies using F18-FDG PET. It should be noted that F18-FDG imaging reflects glucose utilization, whereas low-dose dobutamine echocardiography detects contractile reserve. Although both parameters are markers of myocardial viability, not all viable myocardium may exhibit both contractile reserve and preserved glucose utilization. In patients with severely dysfunctional myocardium and extensive damage on the cellular level, contractile reserve is frequently lost, whereas glucose utilization is preserved (59). Additional studies, evaluating different features of viable myocardium in the same patients, are needed to elucidate changes in myocardial viability after cell therapy.


   Conclusions
Top
 Abstract
 Cell Tracking by Use...
 Imaging to Evalute Functional...
 Conclusions
References
 
The introduction of stem cell therapy for treatment of cell death-related heart diseases is promising, but many issues remain unanswered, including mechanisms of benefit. Both preclinical and clinical studies have used noninvasive imaging techniques for in vivo tracking of stem cells and measurement of effect of therapy. For tracking, direct labeling of cells with radionuclides and super-paramagnetic agents has been reported; in addition, proof of concept of the use of reporter genes for cell tracking has been demonstrated. However, the majority of the methods available for cell tracking are currently only used in animal model studies.

In the clinical setting, various imaging techniques including MRI, nuclear imaging with PET and SPECT, and echocardiography have been used to assess functional effects of cell therapy. Initial studies using these imaging techniques have mostly reported an improvement in LV function and myocardial perfusion/viability, with a reduction in infarct size. However, the evidence is limited, and double-blind, randomized, controlled trials with concurrent imaging techniques are needed to confirm and further elucidate beneficial effects of cell-based therapies. Moreover, future studies will need to assess the reproducibility and accuracy of the imaging methods used for cell tracking and evaluation of the functional effects. Finally, imaging on the molecular level is needed to better understand the effects of cell therapy. This will be realized with the use of PET-CT (or SPECT-CT), which permits co-registration of anatomical (CT) and functional (PET, SPECT) information, and also with 3-T (and higher) MRI.


   Footnotes
 
Helmut Drexler, MD, acted as the Guest Editor for this article.

a Dr. Bartunek, Dr. Vanderheyden, and Dr. Wijns are members of a non-profit research organization that is a founder of Cardio3. Back


   References
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 Imaging to Evalute Functional...
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