positron emission tomography for the evaluation and treatment of cardiomyopathy

Ann. N.Y. Acad. Sci. ISSN 0077-8923

ANNALS OF THE NEW YORK ACADEMY OF SCIENCESIssue: PET/CT Applications in Non-neoplastic Conditions

Positron emission tomography for the evaluationand treatment of cardiomyopathy

Palak Shah, Brian G. Choi, and Ramesh MazhariDivision of Cardiology, George Washington University, Washington, DC

Address for correspondence: Palak Shah, M.D., Division of Cardiology, Medical Faculty Associates, George WashingtonUniversity, Suite 4-417, 2150 Pennsylvania Avenue, NW, Washington, DC 20037. [email protected]

Congestive heart failure accounts for tremendous morbidity and mortality worldwide. There are numerous causesof cardiomyopathy, the most common of which is coronary artery disease. Positron emission tomography (PET) hasan established and expanding role in the evaluation of patients with cardiomyopathy. The specific application of PETto hypertrophic cardiomyopathy, cardiac sarcoidosis, and diabetic cardiomyopathy has been studied extensively andpromises to be a useful tool for managing these patients. Furthermore, evaluating the efficacy of standard treatmentsfor congestive heart failure is important as health care costs continue to rise. Recently, there have been significantdevelopments in the field of cardiovascular stem cell research. Familiarity with the mechanisms by which stem cellsbenefit patients with cardiovascular disease is the key to understanding these advances. Molecular imaging techniquesincluding PET/CT imaging play an important role in monitoring stem cell therapy in both animals and humans.These noninvasive imaging techniques will be highlighted in this paper.

Keywords: cardiomyopathy; stem cells; positron emission tomography; congestive heart failure; molecular imaging

Introduction

Cardiomyopathy (CM) is defined as a disorder ofmyocardial structure or function. Its most frequentconsequence is congestive heart failure (CHF), a“clinical syndrome characterized by symptoms andsigns of increased tissue/organ water and decreasedtissue/organ perfusion” that is a direct result of car-diac muscle pathology.1 As a syndrome, CHF is re-sponsible for worldwide morbidity and mortality.In the United States alone, CHF is responsible forapproximately one million hospitalizations per yearand an expected mortality of 42% at five years.2,3 Atthe age of 40, the lifetime risk of developing CHF isone in five.4 CHF accounts for an annualized healthcare expenditure of $39 billion.5 Therefore, the im-portance of efficient and effective evaluation andtreatment of patients with a CM is essential.

There are numerous etiologies responsible for thedevelopment of a CM, but coronary artery disease(CAD) is by far the most frequent, accounting forapproximately two-thirds of all causes of CM.6 Nu-clear cardiovascular imaging plays an important role

in the diagnosis and management of CAD. The useof single-photon emission computed tomographymyocardial perfusion imaging, (SPECT MPI) hasnearly doubled over the past decade. Similar, albeitless dramatic, growth has been seen in the use ofpositron emission tomography (PET).7

PET was first used to study the cardiovascularsystem in the late 1970s.8–10 PET offers several keyadvantages over SPECT MPI. As compared to single-photon imaging, PET imaging allows for inherentlybetter temporal and spatial resolution due to thecoincident detection of dual photons; these pho-tons are emitted in opposite directions as a resultof the collision of a positron and an electron. Cor-rection of attenuation artifact from fat, breast, anddiaphragm is improved, while artifacts due to at-tenuation correction software are less common.11

The addition of computed tomography (CT) pro-vides additional cardiac anatomic information aswell as improved attenuation correction of PETimages.12 In the realm of cardiovascular imaging,PET is the only currently available modality thatallows quantitative assessment of myocardial blood

doi: 10.1111/j.1749-6632.2011.06017.xAnn. N.Y. Acad. Sci. 1228 (2011) 137–149 c© 2011 New York Academy of Sciences. 137

PET for the evaluation of cardiomyopathy Shah et al.

flow (MBF) using radiotracer kinetics.13,14 Myocar-dial metabolism is increasingly being recognized asan important marker of viability, and metabolismcan be readily assessed using PET radiotracers.15–17

Through PET’s higher resolution imaging, one canaccurately identify changes in the myocardium re-sulting from molecular therapies within a resolutionlimit approaching 4 mm.18 Because the most com-monly used tracers in cardiac PET imaging haveshorter half-lives than their SPECT MPI counter-parts, patients and technicians are exposed to lowerradiation.19 In addition, shorter half-lives of PETradiotracers allow for rapid washout so that re-peat imaging studies with different radiotracers canbe performed on the same patient visit. The mostpressing limitation of wider use of PET imagingappears to be the cost and short half-life of cur-rently available radiotracers. With the developmentof new radiotracers and as the oncologic applica-tion of PET continues to grow, a parallel growth isexpected in the cardiovascular application of PET.Thus, through the aforementioned strengths, PETimaging currently is, and promises to be, an impor-tant tool for the evaluation of patients with CM.

Evaluation of CM

The identification of the etiology of a CM, if pos-sible, is a key step in the evaluation of the pa-tient presenting with a de novo CM. Those patientswith CAD and left ventricular dysfunction whohave demonstrable myocardial viability by nonin-vasive imaging have an 80% reduction in mor-tality if they undergo revascularization.20 Similarresults have been reported in patients undergo-ing PET imaging to plan for revascularization.21–23

Therefore, differentiation of ischemic cardiomy-opathy (ICM) from nonischemic cardiomyopathy(NICM) is important. This can readily and nonin-vasively be accomplished with PET imaging using atracer that allows evaluation of coronary perfusion,such as [13N]ammonia ([13N]NH3) or Rubidium-82 (82Rb), in combination with a tracer that evalu-ates myocardial metabolism, and thus viability, like[18F]fluorodeoxyglucose ([18F]FDG) (Fig. 1). Ini-tially, investigators applied PET imaging in the eval-uation of patients with CM by assessing abnormalmyocardial metabolism alone, without the help ofmyocardial perfusion images.15,24–26 The problemwith relying on myocardial metabolism alone as adiagnostic method is that patients with NICM fre-

quently have metabolic abnormalities in the absenceof infarction. The areas of abnormal metabolism inNICM patients are thought to occur due to my-ocardial fibrosis unrelated to ischemia or infarc-tion.27,28 Moreover, the myocardial fibrosis maybe inhomogeneous and does not necessarily followthe distribution of the coronary vascular anatomy.Therefore, the addition of a myocardial perfusioncomponent to aid in image interpretation was foundto provide improved accuracy over metabolic imag-ing alone.29 This combination imaging with the ra-diotracers [13N]NH3 and [18F]FDG was first usedby Mody et al. in 1991 to help identify patients withICM.29 They reported an overall sensitivity of 100%and a specificity of 80% for differentiating patientswith ICM and NICM.

A detailed review of myocardial viability and thediagnosis of CAD with PET is beyond the scope ofthis paper. The remainder of this review will focuson the role of PET in evaluation and treatment ofpatients with other cardiomyopathies.

Cardiac sarcoidosisSarcoidosis is a granulomatous systemic disease thataffects almost any organ within the body. The firstreport describing the myocardial involvement of sar-coidosis came on a necropsy study performed in1929.30 Sarcoid involvement of the heart was onlyrarely reported in the past, but cardiac sarcoid (CS)is indeed more common than previously appreci-ated.31 About 25% of patients with sarcoidosis willhave evidence of myocardial involvement on au-topsy.32 Despite the relatively high prevalence of my-ocardial sarcoid involvement, only about a third ofthese patients carry the clinical diagnosis of CS.32,33

CS is often a difficult diagnosis to make, becauseno single test has emerged as the ideal diagnosticmodality. Endomyocardial biopsy has an excellentspecificity for detecting CS when noncaseating gran-ulomas are found on histological samples, but un-fortunately due to the inhomogeneous involvementof the myocardium, the reported sensitivity of thistechnique is only approximately 20%.34,35 Numer-ous cardiac imaging modalities have been studied inCS including echocardiography, SPECT, CT, CMR,and PET. They report varying sensitivities and speci-ficities for making the diagnosis of CS, but studiesare difficult to interpret when there is a lack of a goldstandard for the diagnosis.36–53 It is clear, however,that CMR and PET have the highest sensitivity and

138 Ann. N.Y. Acad. Sci. 1228 (2011) 137–149 c© 2011 New York Academy of Sciences.

Shah et al. PET for the evaluation of cardiomyopathy

Figure 1. Gated PET imaging using 82Rb and [18F]FDG to assess perfusion and metabolism, respectively. (A) In a subject withischemic cardiomyopathy, areas of decreased metabolism ([18F]FDG) correspond to areas of decreased perfusion (82Rb), indicatingthat the tissue is nonviable. (B) Another subject with an ischemic cardiomyopathy demonstrating intact metabolism with decreasedperfusion involving the inferior, inferolateral, and inferoseptal walls, indicating that the myocardium is viable in these regions.

specificity of the currently available imaging modal-ities in the evaluation of CS.47,48,50,54

Granulomatous inflammation is a hallmark ofsarcoid. Increased glucose metabolism in inflamedtissues is readily detected with PET.55,56 [18F]FDGuptake in PET has been shown to correlate withtissue inflammation in patients with systemic sar-coid.57,58 Thus, the application of [18F]FDG PETto detect and monitor disease activity in CS seemslogical. The first systematic PET evaluation ofCS was done using combination imaging with[13N]NH3/[18F]FDG by Yamagishi et al. in 2003.47

The use of dual-isotopes allows for detection of per-fusion abnormalities with [13N]NH3 and inflam-matory activity with [18F]FDG. Patients with CSwere found to have both perfusion abnormalitiessecondary to local displacement of myocardiumby granulomatous tissue and increased inflamma-tory activity. Furthermore, those patients who wenton to receive corticosteroid treatment for theirCS had decreased [18F]FDG activity on follow-upPET, but fixed perfusion defects by [13N]NH3 (Fig.2).47 Subsequent studies have confirmed the abil-ity of PET to detect CS, as well as to monitorthe response to corticosteroid therapy.46,48–50,54,59,60

A few researchers have attempted to improve the[18F]FDG PET image quality by either having

patients undergo a prolonged fast or by administra-tion of heparin during image acquisition to reducephysiologic uptake of [18F]FDG and to enhance my-ocardial [18F]FDG uptake in abnormal myocardialsegments.50,60

Future trials are needed to assess the utility of PETin screening asymptomatic patients with systemicsarcoidosis for cardiac involvement in the absenceof clinical symptoms. This is likely to occur if serial[18F]FDG PET is found to be useful in the clinicalfollow-up of patients with systemic sarcoid.61

Hypertrophic CMPerhaps no other genetic CM has been as well stud-ied as hypertrophic cardiomyopathy (HCM). It af-fects approximately 1 out of 500 individuals.62 Over10 genes have been identified that confer risk for thedisease, yet the phenotypic expression of the diseasevaries greatly.63 Some patients with HCM sufferfrom angina, dyspnea, syncope, and sudden car-diac death, while others may be completely asymp-tomatic. Aside from asymmetric septal myocardialhypertrophy and myocardial disarray, which are thehallmarks of the disease, patients with HCM sufferfrom microvascular dysfunction. This was first char-acterized by Maron et al. in 1986, when they studiedthe necropsy specimens of patients with HCM and

Ann. N.Y. Acad. Sci. 1228 (2011) 137–149 c© 2011 New York Academy of Sciences. 139


Figure 2. A subject with cardiac sarcoidosis is studied with 82Rb and [18F]FDG before (A) and after (B) therapy with corticosteroids.The images before therapy showed marked heterogeneous tracer uptake that is improved after therapy.

compared them to patients without HCM.64 Theyfound that patients with HCM, who lacked evidenceof epicardial CAD, had abnormal smooth musclecell proliferation and collagen deposition in the mi-crovasculature. This led to narrowing of the lumi-nal area and thickening of the vessel walls. Further-more, these areas of microvascular dysfunction weremore likely to be associated with severe myocardialfibrosis.

PET offers the unique ability to quantitate mi-crovasculature MBF in the absence of epicardialCAD. The vasodilator dipyridamole has been stud-ied in patients with HCM since 1987.65,66 Studiesusing PET to assess MBF have demonstrated thatpatients with HCM have a blunted response tothe vasodilators dipyridamole and adenosine.67–73

Furthermore, as the severity of microvasculaturedysfunction increases, there is a direct increasein the number of cardiovascular events includingprogressive CHF, ventricular tachyarrhythmias, anddeath.70 Those patients who have the lowest MBFhave an estimated tenfold increased risk of cardio-vascular death compared with HCM patients withmild to moderately reduced MBF.

Only a minority of patients with HCM developsystolic dysfunction.74–76 This is thought to be dueto recurrent myocardial ischemia leading to fibro-sis and progressive left ventricular dilatation.74,75,77

Those patients who develop systolic dysfunction inthe setting of HCM have progressive symptoms andan increased annual mortality of 11% comparedto 1% in the general HCM population.63,76 UsingPET, it has been demonstrated that HCM patientswith impaired dipyridamole-induced MBF are morelikely to undergo abnormal left ventricular remod-eling that leads to ventricular dilatation and systolicdysfunction on long-term follow-up.73 The systolicdysfunction is associated with poor clinical out-comes including worsening CHF symptoms, needfor cardiac transplantation, or CHF-related death.Based on these data, PET represents a promisingresearch modality to help risk-stratify patients withHCM. Such patients with impaired MBF may ben-efit from closer follow-up and perhaps earlier im-plantation of a cardiac defibrillator. This has yet tobe studied in formal clinical trials, however.

Diabetic CMGreater than 30% of the U.S. population is obese,and the prevalence continues to grow.78 Obesity isa strong risk factor for the development of dia-betes. The incidence of diabetes has doubled over thepast few decades.79 Diabetes is clearly a risk factorfor the development of heart failure.80,81 The termdiabetic cardiomyopathy has been used to iden-tify patients with CHF in the absence of CAD.82,83



Diastolic dysfunction is defined as an abnormal-ity in the mechanical function of the heart duringdiastole, in other words, an inability of the heartto relax normally.1 Approximately 50% of patientswith diabetes have evidence of diastolic dysfunctionon echocardiographic studies.84,85 Furthermore, asglycemic control worsens, so does the degree of di-astolic dysfunction.86 Finally, patients with diabetesand CHF represent a special target population asthey have a higher risk of mortality than their coun-terparts without diabetes.87

Early invasive studies have shown that the dia-betic myocardium mainly uses free fatty acids in-stead of glucose as a metabolic fuel.88 Unfortu-nately, the use of free fatty acids as an energysource is less efficient than glucose.89 A similarnoninvasive study was performed in diabetic pa-tients using PET with [11C]glucose, a glucose ana-log, and [11C]palmitate, a fatty acid analog.90 Theseinvestigators found that myocardial use and oxida-tion of fatty acids was increased, while glucose usewas decreased in diabetics as compared to healthycontrols. This phenomenon of decreased myocar-dial glucose use can be reversed in some patientswith a hyperinsulinemic–euglycemic clamp.91 Also,when the peroxisome proliferator-activated recep-tor gamma activators rosiglitazone and pioglitazonewere studied in patients with diabetes, they too im-proved myocardial glucose uptake as measured byPET.92–94 The metabolic derangement that occursin the myocardium of diabetic patients has led tothe hypothesis that this disequilibrium may indeedbe responsible for the development of diabetic car-diomyopathy. Rikzweijk et al. evaluated this theoryin a study using PET in both diabetic patients andhealthy controls.95 They also performed echocar-diograms on their subjects to determine if diastolicdysfunction was present. What they found is thatalthough this patient population had echocardio-graphic parameters suggestive of diastolic dysfunc-tion as well as the expected abnormal myocardialmetabolism seen in diabetics, the two did not ap-pear to correlate.95 Thus, the link between alteredmyocardial metabolism and the development of dia-betic cardiomyopathy warrants further evaluation.

Treatment of CM

Over the past three decades there has been tremen-dous development in the treatment strategiesused for patients suffering from CHF. The use of

proven medical therapies that reduce mortality, suchas angiotensin-converting enzymes inhibitors, beta-blockers, and aldosterone antagonists, has steadilyincreased over this time period.96 In a parallel fash-ion, the usage of device therapies for heart failure,including left ventricular assist devices, implantablecardioverter-defibrillators, and cardiac resynchro-nization therapy (CRT), has dramatically increasedas well.97–99 The median survival for men with CHFhas increased from 1.3 years in 1986 to 2.3 years in2002, with similar but less significant improvementsoccurring in women.96 Despite the improvement inoutcomes, the mortality from heart failure contin-ues to be substantial.

Patients with a CM often have the presence ofan intraventricular conduction delay (IVCD), in-dicative of dyssynchronous depolarization of theleft ventricular myocardium. Early clinical inves-tigations have shown that CRT in CM patientswith depressed ejection fraction and marked IVCDhelps improve left ventricular function while re-ducing myocardial oxygen consumption, implyingimproved cardiac efficiency.100 Robust, large-scaletrials have shown that CRT devices lead to re-duced CHF-associated hospitalizations, morbidity,and mortality.101–104 Yet, many patients who receivethese devices are considered to be nonresponders;thus, an improved method of screening is neededto assess which patients may benefit from this ex-pensive therapy.105 PET is an excellent modality tohelp evaluate such patients. Using [18F]FDG-basedPET, Nowak et al. were able to demonstrate de-creased septal to lateral wall [18F]FDG uptake inpatients with a CM and IVCD.106 A follow-up PETscan was performed after the insertion of a CRTdevice that revealed normalization of this ratio. Asimilar study was performed using [11C]acetate toevaluate myocardial oxygen metabolism instead ofglucose metabolism. These investigators found thatCRT devices did not increase myocardial oxygenmetabolism, despite an overall improvement in sys-tolic function.107 Based on these findings, it is pos-sible to conclude that CRT devices improve left ven-tricular systolic function, homogenize myocardialglucose uptake, but do not increase myocardial oxy-gen metabolism or result in reduced cardiac effi-ciency. It has been shown that patients with CHFwho undergo formal exercise training programshave improvement in exercise tolerance and leftventricular function.108 Of interest, these changes



in functional status are accompanied by a reducedmyocardial oxygen metabolism and improved car-diac efficiency as measured by [11C]acetate PET.108

Cardiac stem cell therapy

Great strides have been made in the treatment ofCHF. Unfortunately, the morbidity and mortalityfrom this disease continues to be significant despitemaximal medical and device therapy. Furthermore,only a few forms of CM are completely reversible,and most therapies only halt the progression of dis-ease without curing it. The promise of therapies thatcan truly repair and regenerate the myocardium isexciting. Stem cells are a key discovery in this regard.Their ability to be engrafted, to reproduce, and todifferentiate into the myocardium and endothelialcells hopes to be a cure for CHF. The old dogma thatthe heart was a terminally differentiated organ with-out an ability to regenerate itself is being contestedby the suggestion that the heart has its own residentbody of stem cells, cardiac progenitor cells, that havea limited ability to regenerate myocytes.109

Overview of clinically used stem cellsVarious forms of stem cells have been studied in themyocardial tissue. The four that have been studiedin clinical trials include skeletal myoblasts (SMs),bone marrow–derived mononuclear cells (BMCs),progenitor cells (PCs), and mesenchymal stem cells(MSCs). We will give a brief overview of these celltypes here; for those interested in reading more re-garding this topic, an excellent review is available.110

Normal human muscle contains SMs that canreplicate to assist with skeletal muscle repair. Thesecells can be collected with simple muscle biopsy,cultured in vitro, and then implanted into the hu-man myocardium. Furthermore, the cells are resis-tant to ischemia, making them ideal for scar-basedtherapies where blood flow is limited. The first clin-ical trial of allograft SMs for ICM was performedby Menasche et al.111 Patients with ICM had scar-ring identified by a combination of [18F]FDG PETand dobutamine echocardiography; these areas ofscar were then injected with SMs during a coronaryartery bypass procedure. The majority of scarredareas that had received therapy with SMs showedan improvement in myocardial contractile re-sponse, with the overall cohort experiencing an 8%increase in ejection fraction, from 24% to 32%.111

Of paramount clinical concern, however, was the

high number of ventricular arrhythmic events inpatients receiving SMs. The high rate of ventric-ular arrhythmias may be secondary to the inabil-ity of SMs to form gap junctions with the cardiacmyocytes and thus prevents electrically coupled de-polarization of the ventricles, making the ventriclesmore disposed to the development of ventricular ar-rhythmias. To verify these exciting results, a larger,placebo-controlled, multicenter trial was conductedlater with close to 100 patients with ICM.112 Unfor-tunately, this trial failed to demonstrate a benefitof SMs therapy, indicating that most of the benefitconferred from the earlier trial was likely secondaryto the revascularization of patients with CAD andICM, rather than therapy with SMs. Furthermore,the proarrhythmic potential of SMs warrants cau-tion in future cardiac applications of this celllineage.112

The bone marrow continuously produces cells ofhematopoietic lineage throughout the human lifecycle. Thus, the ability to harvest autologous BMCsthat are nonantigenic and undergo constant repli-cation to help produce cardiac myocytes has beenan interesting prospect. Unfortunately, it is not clearthat BMCs can transdifferentiate into cardiac my-ocytes.113 It is likely a paracrine effect, rather thantransdifferentiation of BMCs, that accounts for theirbeneficial effect in the human myocardium.114,115

The effect of BMC therapy on left ventricular func-tion after acute myocardial infarction (AMI) wastested in the BOOST trial (bone marrow trans-fer to enhance ST-elevation infarct regeneration).116

Patients who presented with ST-segment elevationMI and underwent successful primary percutaneouscoronary intervention (PCI) with stent placement,were then randomized to receive intracoronary in-fusion of autologous BMCs versus standard carealone. The investigators found that BMC therapyimproved left ventricular ejection fraction by an ab-solute difference of 4.7% at six months, but thesame benefit was not apparent at the 18-monthor five-year follow-ups.117,118 Stem cell therapy hasalso been tested by Perin et al. in patients with ad-vanced ICM.119 This group studied patients withreversible ischemia demonstrated by SPECT MPI,who were not deemed candidates for any form ofrevascularization therapy, and then injected BMCsdirectly into the myocardium that was deemed to beischemic. The patients who received therapy withBMCs not only had an improvement in ejection



fraction, but also had reduced perfusion defects onfollow-up SPECT MPI with a reduction in subse-quent CHF-related symptoms. On one-year follow-up, these patients had sustained benefit in termsof improved myocardial perfusion, exercise capac-ity, and reduced CHF symptomatology, but similarto the BOOST trial, the sustained improvement inejection fraction was no longer seen.118,120 This sug-gests that the benefit derived from the BMCs wasnot likely due to new cardiac myocyte formation,but rather angiogenesis that improves blood flow toischemic tissues.

Another line of hematopoietic stem cells is thePCs. These cells are found in the peripheral cir-culation and bone marrow. They contribute toneovascularization and can differentiate into en-dothelial cells. Although they too do not trans-differentiate into cardiac myocytes, they likelyrelease paracrine factors that promote angiogen-esis.121,122 In REPAIR-AMI (the reinfusion of en-riched progenitor cells and infarct remodeling inAMI), patients who have successfully undergoneprimary PCI were randomized early after their MIto receive bone marrow–derived PCs or a placebomedium.123 There again was an absolute differencein ejection fraction of 3.9% at four months follow-up. Perhaps more meaningful was the reduction inclinical cardiovascular events seen in those patientsreceiving PCs at one-year follow-up.124 The mainlimitation of this trial was that the ejection fractionwas assessed by left ventricular angiography, whichhas a poor accuracy compared to other availablemodalities.

Finally, the MSCs are the last stem cell popula-tion to be used clinically for the treatment of car-diovascular disease. These cells are isolated fromthe stroma of the bone marrow and have beenshown to differentiate into adipocytes, chondro-cytes, and osteocytes.125 MSCs are also thought tohave antiinflammatory and antiapoptotic proper-ties with the added advantage of being immunolog-ically silent.126,127 Another exciting feature of MSCtherapy is the ability of these cells after intravenousinjection to migrate to the heart, without the needfor direct myocardial or coronary inoculation.128

Utilizing a post-MI animal model for MSC therapy,Amado et al. were able to demonstrate improvedmyocardial thickness and reduced scar formationin the infarct zone.129 Furthermore, there wasimproved contractility of these infarcted regions in

those animals that received treatment with MSCscompared to controls. An early phase I clinical trialof intravenous MSCs for adjunctive treatment inpatients with AMI was recently conducted.130 Pa-tients who had a recent MI and had undergonesuccessful PCI were then randomized to placeboversus MSCs therapy. On follow-up, the patientswho had received MSCs had improved ejection frac-tion by cardiac MR at one year, as well as reducedventricular arrhythmias compared to the placebogroup.130

Molecular imagingAlthough clinical trials using stem cell therapy haveshown some promise, much remains to be answeredin terms of how stem cells support myocardial func-tion: is it the paracrine effect? Does neovascular-ization drive myocardial recovery? Are stem cellsable to transdifferentiate into cardiomyocytes? Dostem cells signal resident cardiac progenitor cells?131

Furthermore, how we track delivery of cells, theirreplication, engraftment, and retention over timeremains to be studied. Improved techniques totrack delivered stem cells and their daughter cellsare needed. Currently available molecular imag-ing techniques include direct labeling with radioac-tive tracers or iron particles, reporter genes, andnanoparticles. Direct labeling with iron particles isdone for tracking cell therapy using magnetic reso-nance imaging (MRI) technology.132,133 MRI has su-perior spatial resolution and allows imaging withoutan associated radiation risk, but lacks the sensitiv-ity to assess smaller cell populations especially deepinside tissues. Also, many patients with end-stageCM have had mechanical interventions (e.g., defib-rillator, left ventricular assist device) that, in turn,preclude the ability to use MRI. Labeling with ra-dioactive tracers on the other hand has an excellentsensitivity for detecting smaller cell populations andcan safely be used in patients with metallic devices,but unfortunately the spatial resolution is inferiorto MRI. The spatial resolution of nuclear imagingis likely to improve if further integration is seen incardiovascular research of combined PET/CT imag-ing. In addition, direct labeling of cells is easier toperform than some of the other aforementionedtechniques, but is limited because decoupling of thelabel and cell can occur. For example, iron particlescontinue to be detected by MRI weeks after their hostcells have died.133 Furthermore, the short half-life of



currently available radioactive tracers prevents serialimaging to assess cell retention or permit long-termcell tracking.

The reporter gene method is a promising label-ing technique that uses a viral vector to transportspecific protein-encoding genes.134,135 As these vi-ral vectors transfect stem cells, the reporter gene isthen incorporated into the genome of the stem cell.When the genome of these stem cells is transcribedand translated, specific proteins are produced. Theseproteins can then be targeted by specific probes, thusallowing for in vivo visualization of reporter gene in-fected stem cells.136 Furthermore, as those stem cellsreplicate and produce daughter cells, these cells toowill have mRNA that can be transcribed to producethese specific target proteins. Finally, with the re-porter gene method, only viable cells will be imagedand repeat imaging can be done without limitationdue to tracer half-times as reinjection of the probecan be done at any time.137 The main limitationsof the reporter gene technique are that it is techni-cally challenging and time-intensive. Furthermore,the safety of such cell transfection and how it affectscell function in humans remains unclear. Finally, la-beling with nanoparticles such as quantum dots hasbeen accomplished in living cells, but this technol-ogy is still in its infancy.138,139

Challenges of stem cell therapy and the roleof PET imagingMost clinical trials studying stem cell therapy haveused ejection fraction, myocardial perfusion, andviability as surrogates for improvement in overallmyocardial performance. Yet, the true benefit con-ferred by stem cell therapy is still unclear. Molecularimaging techniques described earlier will need to beincorporated into animal and clinical stem cell tri-als to help to better understand the molecular basisfor the clinical benefit of stem cell therapy. Indeed,only a small fraction of delivered stem cells are ac-tually retained by the myocardium.128,140,141 Manyquestions remain to be answered regarding stem celltherapy. Do stem cells transdifferentiate into car-diac myocytes? Are the paracrine effects responsiblefor most of the myocardial recovery seen in clinicaltrials? What cell type and dosage of cells is appro-priate for therapy? Is there a way to augment cellengraftment and replication? Can we stimulate resi-dent cardiac progenitor cells to replicate? When, af-ter myocardial infarction, should cells be delivered?

What is the most appropriate route for the deliveryof cells and how do we create an environment thatpromotes cell survival? Finally, how can we tracksuch therapies both in animal and in human mod-els acutely and over time?

An ideal imaging modality would help elucidatesome of these questions. It would allow molecularimaging to occur in the animal model with easytranslation to human studies and subsequent ap-plication in the clinical arena. PET has great trans-lational potential from imaging in small animalswith commercially available microPET systems toimaging adults using PET/CT systems.142–146 Also,since stem cell therapy appears to improve MBFthrough angiogenesis, the ideal imaging tool wouldnot only track stem cells, but also allow accurateassessment of MBF. PET has the advantage of be-ing the only currently available imaging modalitycapable of quantification of MBF, although pre-liminary studies in this regard with MRI are nowbeing conducted.147 It is important to recognizethat SPECT MPI only allows for detection of dif-ferences in myocardial perfusion, and does not ac-tually quantify MBF. Another key advantage of PETover SPECT imaging is the superior spatial and con-trast resolution. Finally, as most current applica-tions of stem cell therapy appear to benefit patientswith an ICM, assessment of viability is the key; inthis regard, PET is the most sensitive of currentlyavailable imaging modalities for detecting viablemyocardium.148

Conclusion

Of the currently available imaging modalities, PEThas many unique characteristics. The ability of PETto quantify MBF is an important tool for assessmentof patients with HCM as well as tracking angiogene-sis in ischemic tissue receiving stem cell therapy. Anunderstanding of myocardial metabolism throughPET imaging not only provides an excellent modal-ity for detection of viable myocardium, but also canbe used to assess disease activity in patients with CS.Furthermore, diseased myocardium represents anideal target for stem cell therapy. Molecular imag-ing is a field that is in development; the ability ofradiotracers to track stem cells in animal modelsand then in humans is important for rapid trans-lation of research from the bench to the bedside.MicroPET and PET imaging systems will be key tothis translation.



Acknowledgment

The authors are sincerely thankful to Dr. Ajith Nairfor help in the acquisition of images used in writingthis review.

Conflicts of interest

The authors declare no conflicts of interest.

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