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S T A T E - O F - T H E - A R T P A P E R

Targeted Metabolic Imaging to Improve theManagement of Heart Disease

Moritz Osterholt, CANDMED,* Shiraj Sen, BA,* Vasken Dilsizian, MD,†Heinrich Taegtmeyer, MD, DPHIL*

ouston, Texas; and Baltimore, Maryland

Tracer techniques are powerful methods for assessing rates of biological processes in vivo. A case in point

is intermediary metabolism of energy providing substrates, a central feature of every living cell. In the

heart, the tight coupling between metabolism and contractile function offers an opportunity for the

simultaneous assessment of cardiac performance at different levels in vivo: coronary flow, myocardial

perfusion, oxygen delivery, metabolism, and contraction. Noninvasive imaging techniques used to iden-

tify the metabolic footprints of either normal or perturbed cardiac function are discussed. (J Am Coll

Cardiol Img 2012;5:214 –26) © 2012 by the American College of Cardiology Foundation

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In order to contract under constantly changingenvironmental conditions, the healthy heartderives its energy from a variety of oxidizableorganic compounds (1). When myocardial en-ergy demands are increased acutely, the heartmaintains the balance between its energeticsupply and demand by shifting fluxes throughexisting metabolic pathways (2,3). Sustainedincreases in myocardial energy demand result inmetabolic adaptations at a transcriptional levelthrough selective up-regulation of the synthesisand degradation of the enzymes that collectivelymake up metabolic pathways (4). In short, astriking system of checks and balances regulatescontractile function in the heart and metabolismis at the center of the whole system.

Since the 1980s, the study of cardiac metab-olism in the laboratory has been leveraged byclinicians using noninvasive imaging to distin-guish heart muscle that is reversibly dysfunc-tional (viable myocardium) from muscle that is

From the *Department of Internal Medicine/Division of CardioloHouston, Texas; and the †Department of Diagnostic Radiology anCenter, Baltimore, Maryland. The authors have reported that theypaper to disclose.

Manuscript received August 16, 2011; revised manuscript received No

irreversibly dysfunctional (scar tissue) (5). Theassessment of regional myocardial metabolismwas first appreciated as a tool to guide therapeuticdecisions for revascularization in patients withchronic ischemic left ventricular dysfunction.Here, the premise was that restoration of bloodflow to viable ischemic tissue will result in resto-ration of oxidative metabolism and, therefore,normal contractile function. Similar imagingtechniques are now explored to identify prospec-tively patients with reversible left ventricular dys-function in order to improve both quality of lifeand outcome (6,7).

Regulation of Metabolism inNormal and Failing Hearts

The uptake of oxidizable fuel is tightlymatched to the contractile work performed bythe heart (8). Because oxygen extraction by theheart is nearly complete, increased rates of

University of Texas Medical School at Houston,uclear Medicine, University of Maryland Medicale no relationships relevant to the contents of this

vember 14, 2011, accepted November 28, 2011.

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oxygen consumption can only be met by an increasein coronary flow (9). The normal heart oxidizes fatin preference to carbohydrates (the Randle hypoth-esis) (10), but it increases carbohydrate oxidationwhen stressed (11). When myocardial blood flow isimpaired, the balance between cellular metabolismand contractile function is perturbed. The decreasein coronary flow and concomitant reduction inoxygen delivery triggers specific and coordinatedresponses in gene expression, including activation ofhypoxia-inducible factor 1-alpha (12) and the reac-tivation of the fetal gene program (13), both ofwhich improve the cardiomyocytes’ tolerance toischemia. Collectively, these changes represent theheart’s adaptive processes resulting in cell survival, aphenomenon that we termed “programmed cellsurvival” some time ago (14,15). The term pro-grammed cell survival contrasts programmed celldeath or apoptosis, which occurs in the maladapted,failing heart. The metabolic derangements in thefailing heart have been reviewed earlier (16,17). Wehave proposed that the nonischemic, failing heart isdrowning in fuel (18), and there is considerablemetabolic heterogeneity in the failing human heart.Both are areas of active research and beyond thescope of this review.

Beyond supporting the metabolism of energy-providing substrates, proteins that regulate meta-bolic pathways in the heart turn over themselves, asdo sarcomeric proteins, cytoskeletal proteins, andother cellular components that are necessary forcardiac maintenance and growth. When subjectedto stress, the heart undergoes hypertrophy, a processthat demands increased energy supply. A largeamount of this energy is likely required to fuelprotein synthesis and protein quality control (19),suggesting the need for the cardiomyocyte to con-tinually renew itself from within during times ofgrowth. Whereas regression of left ventricular hy-pertrophy has been associated with improved con-tractile function, its effects on myocardial energeticshave yet to be characterized with noninvasive met-abolic imaging.

Which Tracers for Which Pathways?

Nuclear metabolic imaging uses targeted radiotrac-ers to assess flux through specific metabolic path-ways (by quantifying either the flux of energy-providing substrates or the steady-state metabolites). Itis convenient to follow energy transfer in the heartmuscle cell from the circulation (substrate and
oxygen delivery) to the cross bridges (energy use)
through a series of moiety-conserved cycles (Fig. 1).Specific radiotracers are available to assess perfu-sion, substrate uptake, and delivery, as well as Krebscycle turnover (oxygen consumption). We haverepresented the family of radiolabeled tracers by redarrows. In addition, we have highlighted the met-abolic imaging modalities by magnetic resonancespectroscopy with either stable isotopes (e.g., car-bon C 13) or phosphorous P 31 in the blue circles.Calcium (Ca2�) is not an imaging agent, but theion has been included because it is the signal thatlinks contraction and mitochondrial respiration(20). Radiotracer retention and/or metabolism areassessed by noninvasive techniques, such as single-photon emission computed tomography (SPECT)and positron emission tomography (PET).

Two classes of radiotracers are currentlyused to trace metabolic activity: labeledsubstrates or substrate analogs. Labeledsubstrates are taken up by heart muscleand either rapidly cleared or retained,whereas substrate analogs are taken up andretained only (Fig. 2). Both will be dis-cussed in the context of their usefulness.

To assess fatty acid use, earlier studiesused the labeled substrate carbon C 11(11C)–palmitate. After its uptake into theell and activation by binding to coenzyme, 11C-palmitate undergoes beta-oxidation,ltimately leading to the release of 11CO2.

However, this technique requires a PETcamera and an on-site cyclotron. As SPECTcameras were already available to the major-ity of nuclear cardiologists, the focus turnedon the development of SPECT tracers forfatty acid oxidation. One of them is iodine I123–beta-methyl-p-iodophenyl-pentadeca-noic acid (123I-BMIPP), a substrate ana-log that is rapidly taken up into the cardi-omyocytes and that shows prolonged retention dueto limited catabolism.

The current gold standard for evaluating glucosemetabolism is 2-deoxy-2-(18F) fluoro-D-glucose(18F-FDG) PET. 18F-FDG is a glucose analog thatcompetes with glucose for phosphorylation by hexoki-nase. Once phosphorylated, it is trapped inside the celland can neither be further metabolized, nor exportedback out of the cell. We have demonstrated previously(21) the retention of 18F-FDG in the isolated per-used heart at a constant, intermediate workload (Fig. 3).

Hearts were perfused with a buffer containing18F-FDG for 60 min. During this time, radioactiv-

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the retention of the tracer by the heart when theperfusate was switched to a tracer-free perfusate at60 min (Fig. 3, arrow). The drop in tissue radioac-tivity was caused by the washout of tracer from theventricles and vascular and extracellular spaces.

Energy Is Transferred Along a Series of Conserved Cycles,t Coronary Circulation and Ending at Cross-Bridge Formationtile Elements

lease from the sarcoplasmic reticulum triggers calcium uptakeitochondria and activation of dehydrogenases in the Krebs cycle.ed tracers in combination with single-photon emission computedy or positron emission tomography (red arrows) and nuclearesonance spectroscopy (blue cycles) can assess various cyclesely in vivo. ATP � adenosine triphosphate; NAD(P)H/H� �

icotinamide adenine dinucleotide (phosphate); FADH2 � reducedine dinucleotide; PCr � phosphocreatine.

Schematic Overview of the Fate of Labeled Substrates andAnalogs

ed carbon C 11 (11C) substrate is taken up into the cell andcomplete oxidation, eventually leading to the release of 11CO2.uptake into the cell, substrate analogs labeled with fluorine F 18ine I 123 (123I) are partially metabolized and then retained. Thef perfusion tracers require preserved cellular metabolism to bey the cell. Substrate oxidation rates can also be monitored using

15 15
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Also, note that tracer uptake was linear with time byPatlak analysis (Fig. 3, see inset).

Whereas the imaging of glucose and fatty acidmetabolism in the heart has been well established inthe past, imaging of amino acid metabolism hasreceived less attention. In comparison to fatty acidsand carbohydrates, amino acids are a more heteroge-neous group of small organic compounds. The func-tion of amino acids as building blocks for proteins andthe intermediary metabolism of amino acids in thebody was first investigated with stable isotopes bySchoenheimer in 1942 (22). The carbon skeleton ofamino acids may enter the citric acid cycle andreplenish the pool of its intermediates by a processtermed anaplerosis, or be used for anaerobic energyprovision (23). In 1954, Bing et al. (24) reported thatamino acids were extracted from the coronary bloodand suggested that “a considerable fraction of theoxygen consumption of the heart can be ascribed tothe breakdown of amino acids.” The intermediarymetabolism of amino acids is complex. However,under aerobic conditions many amino acids, includingthe branched chain amino acids (BCAA) leucine,isoleucine, and valine, are oxidized in the Krebs cycle(Fig. 1). The BCAA are essential amino acids withmultiple roles in energy balance, nutrient signaling,and protein homeostasis (25). The rate-limiting stepin their catabolism is the alpha-ketoacid dehydroge-nase reaction, an enzyme regulated by phosphoryla-tion and dephosphorylation (26). Huang et al. (27)recently reviewed the role of defects in BCAA me-tabolism in heart disease. Despite the physiologicalimportance of BCAA metabolism (and myocardialprotein turnover in general), as yet no metabolicimaging strategies have been applied in the heart.

In contrast, amino acid metabolism in the ische-mic heart has been investigated with 11C-glutamate. The rationale for this tracer is given bythe anaerobic metabolism of glutamate to bothalanine (28) and succinate (23). At the same time,we observed enhanced extraction of glutamate andenhanced release of alanine by hearts of patientswith coronary artery disease (29). We suggestedthat this pattern was part of an adaptive process,where pyruvate is converted into alanine by thetransfer of an amino group from glutamate, therebyreducing the formation of lactate out of pyruvate,which would ultimately inhibit glycolysis and thusanaerobic adenosine triphosphate production. Al-though the potential of using labeled amino acidsfor cardiac PET imaging was recognized 30 yearsago (30), only a few investigators have used this

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ischemia. Several studies have assessed the uptakeof nitrogen N 13 glutamate in the ischemic heart,reporting either increased (31,32) or unchangedrates of uptake (33), relative to blood flow tracers asnitrogen N 13 ammonia or thallium Tl 201 (201Tl).More recent studies used 11C-methionine for PETnalysis of cardiac tissue after myocardial infarctionMI) (34). The investigators reported increasedptake of 11C-methionine in infarcted areas during

the acute phase after MI, whereas 201Tl and 18F-FDG uptake were reduced. Thus, the assessment of11C-methionine uptake can be useful in monitoringthe remodeling of the heart after MI. With thecurrent notion that changes in amino acid metab-olism are an “underappreciated culprit” of heartdisease, rather than just an epiphenomenon (27),studies addressing and validating the imaging ofcardiac amino acid metabolism by using labeledamino acids are needed more than ever.

Metabolic Remodeling in MI

The heart protects itself from insufficient oxygensupply by down-regulating mitochondrial oxidativemetabolism. Moderate ischemia (75% reduction incoronary flow) shifts myocardial energy metabolismto an anaerobic state (35). During severe ischemia(90% reduction in coronary flow), myocardial glu-cose extraction increases while glucose uptake re-mains the same (36), at least until the degree ofischemia becomes so severe that substrate deliveryand glycolysis are both inhibited by the accumula-

Figure 3. Diagram Showing Linear Increase of Radioactivity in t18F-Fluorodeoxyglucose-Containing Buffer

Note that tissue radioactivity remains constant after a tracer-free buexperiment (not shown). Patlak analysis shows linear tracer uptake

tion of lactate (37). During prolonged severe ische-

mia, the decline of glucose uptake may be attenuatedby various interventions protecting the heart againstischemic injury, such as an increase in the extracellularglucose concentration or the addition of insulin (38).Moreover, transcript levels of glucose transporters arealso increased (39–41). In the absence of adaptivechanges in metabolism, the resultant energy deficitultimately leads to cell death, either by apoptosis ornecrosis (14). Hence, acute and chronic metabolicadaptation to a temporary or sustained reduction incoronary blood flow conserves energy to protect thestructural and functional integrity of the myocardium.Reversible metabolic changes, as a feature of sustainedmyocardial viability, will occur in the setting of dimin-ished but not absent regional myocardial blood flow.

Assessment of Myocardial Viability

To date, much has already been written about theassessment of myocardial viability (42). The prin-ciple is clear. Any transformational change in re-sponse to an altered environment requires a livingor “viable” tissue. Let us consider the following: Asalready outlined, the oxygen-deprived heart exhibitsdrastic changes in its metabolism leading to thedevelopment of left ventricular dysfunction. Assess-ment of myocardial viability is needed in a situation,when left ventricular dysfunction can be eitherpermanent (due to myocardial cell death and for-mation of scar tissue) or reversible (in hibernatingmyocardium, which is ischemic but still viable). Thebenefit of revascularization for patients with coro-

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increased with increasing amounts of hibernatingmyocardium (43). Metabolic imaging techniquessuch as 18F-FDG PET can identify the extent of

ibernating myocardium and, therefore, help tossess the benefit of revascularization in these pa-ients (44).

By definition, hibernating myocardium showshronic contractile dysfunction in the setting ofeduced coronary flow reserve. After revasculariza-ion, myocardial function is restored, paralleled byn increase in coronary flow reserve (45). Hibernat-ng myocardium can be assessed noninvasively with

variety of radiolabeled markers using differentechniques. Whereas SPECT tracers, like 201Tlhloride and technetium Tc 99m (99mTc)–labeled

tetrofosmin and 99mTc sestamibi, are primarily usedto assess blood flow, the uptake and retention ofthese agents inside the cell still requires intact cellmembranes and viable cells. Hence, thallium and99mTc-labeled perfusion tracers can be used forviability assessment as well. These flow tracers whenadministered under resting conditions delineate pres-ence or absence of scar tissue and its amount. As such,the information obtained with these flow tracers isanalogous to that available through late contrast-enhanced magnetic resonance imaging where theamount of residual nonenhancing myocardium (orscar tissue) contains, similar to the perfusion defectseverity, predictive information on the potential forfunctional recovery (46). However, beyond identifyingregional blood flow, thallium differs from other flowtracers as being a monovalent cation with biologicproperties that are similar to potassium. Like potas-sium, thallium is transported across the myocellular

Figure 4. PET Scan Showing Hibernating Myocardium, Revealin

(A) Blood flow imaging using rubidium Rb 82 (82Rb) in short-axis vibasal slices in the apical, inferior, inferolateral, and septal regions ocose–(18F-FDG) labeled positron emission tomography images acquabnormally perfused myocardium, except for the anteroseptal regio
from Taegtmeyer and Dilsizian (58).
membrane via the sodium-potassium adenosinetriphosphatase transport system. Whereas the initialextraction and distribution of thallium in the myocar-dium are primarily a function of blood flow, the lateredistribution phase of thallium is a function of re-gional myocardial potassium space (as the radiotracerhas equilibrated between blood and myocytes). Thus,differences in thallium distributions between the early(myocardial perfusion phase) and delayed images re-flect hypoperfused but viable (in the true sense of theterm) myocardium. At the same time, although myo-cardium can be severely hypoperfused, regional in-crease in glucose extraction via glucose transporterprotein type 1 results in up-regulated glucose uptake(termed a mismatch pattern) (Fig. 4). This mismatchpattern is an indicator for hibernating myocardium,which can be salvaged by the restoration of blood flow.Therefore, metabolic imaging of myocardial viabilitymay assist the early identification of patients whowould benefit from revascularization therapies. Thiswould decrease the risk/benefit ratio of revasculariza-tion and improve the patient’s outcome and prognosis.

Imaging Cardiac Metabolism toDetect Antecedent Ischemia

The detection of even subtle metabolic alterations inthe ischemic myocardium by metabolic imaging wasfirst shown in a canine model of partial coronary arteryocclusion and rapid atrial pacing (47). In subsequentocclusion-reperfusion studies, prolonged metabolic al-terations were observed after 30 min of occlusion.These metabolic changes persisted for several weeksthereafter (48–51). The studies served as the experi-

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mental basis of subsequent clinical studies in whichpersistent reductions in fatty acid metabolism could bedetected long after the resolution of the perfusionabnormality and ischemia (52–58). Thus, the applica-tion of a metabolic radiotracer for imaging, as opposedto a perfusion tracer, potentially extends the scope fornoninvasive imaging of an ischemic event beyond theresolution of symptoms and allows monitoring long-term effects. The concept applies to tracers or traceranalogs of both long-chain fatty acids and glucose.Their uptake by previously ischemic heart muscle iseither decreased (in the case of fatty acids) or increased(in the case of glucose).

An exciting development in this field is the use of123I-BMIPP to assess fatty acid metabolism withSPECT. In an open-label phase 2A clinical trial,patients with exercise-induced ischemia on a clini-cally indicated thallium SPECT study underwentrest 123I-BMIPP SPECT imaging within 30 h ofhe exercise treadmill study (52). 123I-BMIPP wasble to detect antecedent ischemic abnormalitywith 91% agreement between 123I-BMIPP uptakend retention under resting conditions and 201Tl

imaging under stress conditions). These findingswere complemented by studies that interrogated thebenefits of assessing altered glucose metabolism inpatients undergoing exercise treadmill testing using18F-FDG (53,54). A metabolic switch from pre-dominant fatty acid use to predominant glucose useseems pivotal in preserving myocardial viability andlikely represents the earliest adaptive response tomyocardial ischemia (53). Applying a dual-isotope99mTc sestamibi and 18F-FDG simultaneous injec-ion and acquisition protocol, investigators havehown that a metabolic switch from fatty acid tolucose use occurs promptly when myocardial isch-mia is induced during exercise. Moreover, thexercise-induced metabolic switch to glucose mayersist for 24 h, despite restoration of blood flow atest (54,55). Together, these reports with fatty acidnd glucose analogues suggest an interdependencef the increased glucose uptake and the diminishedatty acid uptake. Whether there are temporalifferences between the 2 processes cannot be ad-ressed conclusively, because the 2 radiotracers

123I-BMIPP and 18F-FDG) were not injected athe same time and in the same patient.

In a recent multicenter clinical trial, patientsresenting to the emergency department with sus-ected acute coronary syndrome were imaged with

123I-BMIPP within 30 h of symptom cessation(56). The initial clinical diagnosis was based on
symptoms, electrocardiographic changes, and ele-
vated serum troponin levels, whereas the final di-agnosis was determined on the basis of all availabledata (including coronary angiography and stressSPECT) but not 123I-BMIPP SPECT. Final di-agnoses were adjudicated by a blinded committeeinto “positive for acute coronary syndrome,” “inter-mediate likelihood of acute coronary syndrome,” or“negative for acute coronary syndrome.” Comparedto the clinical impression alone, the combination of123I-BMIPP with the initial clinical diagnosis in-creased sensitivity for identifying patients withacute coronary syndrome, negative predictive value,and positive predictive value, with the same speci-ficity. The findings suggest that the addition of123I-BMIPP imaging data to the clinical impressionprovides incremental value toward the early diag-nosis of acute coronary syndrome in the emergencydepartment. These results are consistent with ear-lier findings in patients with acute chest pain whounderwent coronary angiography, in which thesensitivity of 123I-BMIPP for detecting an obstruc-tive coronary artery disease or provocable spasm was74%, when 123I-BMIPP imaging was carried out

ithin 3 days of presenting symptoms (57). Delayedecovery of fatty acid metabolism as assessed byPECT for up to 30 h after the resolution ofransient myocardial ischemia, provides the poten-ial for diagnosing antecedent myocardial ischemia,

phenomenon that we have termed “ischemicemory” or “metabolic stunning” (58).

Metabolic Remodeling of the Heart inDiabetes and Obesity

Noninvasive imaging also provides distinct advantagesto studying the effects of systemic metabolic diseases,such as diabetes and obesity, on the heart. Theintroduction of new animal models of insulin resis-tance and type 2 diabetes has resulted in a deeperunderstanding of the biochemical derangements un-derlying metabolic and structural remodeling of themyocardium. We have proposed that metabolic re-modeling precedes, triggers, and maintains functionaland structural remodeling, all of which can be tracedby noninvasive imaging techniques (2). With diabetesand obesity, fatty acid delivery to the heart is in-creased. In combination with increased incorporationof fatty acid translocase into the plasma membrane(59), excess fatty acid supply results in increasedintracellular levels of fatty acids. After being activatedto acyl coenzyme A, fatty acids can serve manypurposes, including energy production (via mitochon-
drial beta-oxidation), post-translational protein mod-


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ification, or triglyceride synthesis (60). However, car-diomyocytes have only a limited capacity to storetriglycerides and an increase in triglyceride levels in theheart can be used as an indicator of a deleteriousimbalance between fatty acid uptake and oxidation(61) that eventually culminates in lipotoxicity. Indeed,myocardial lipid overload induces a lipotoxic cardio-myopathy even in the absence of systemic perturba-tions in fatty acid metabolism (62).

In patients with impaired glucose tolerance, myo-cardial steatosis was found using hydrogen H 1 mag-netic resonance spectroscopy and shown to precedethe onset of type 2 diabetes and cardiac dysfunction(63). Whereas increased intracellular triglyceride levelsare considered more as a marker rather than a medi-ator of lipotoxicity (64), increased levels of acyl coen-zyme A have several detrimental effects. 1) Besidetriglycerides, levels of diacylglycerol (DAG) are en-hanced, which has been implicated in the activation ofprotein kinase C theta. Chronic activation of proteinkinase C theta impairs insulin signaling by phospho-rylating insulin-receptor substrate 1 on serine residues(65,66). 2) Concentration of ceramide, potentiallycardiotoxic due to its role in apoptotic signaling, isincreased, which is associated with the development ofcardiomyopathies in diabetes and obesity (67).3) Excess fatty acids and their oxidation are associated

Figure 5. Pathogenic Factors Contributing to the Development

See text for further discussion. Reprinted, with permission, from Dil
LVH � left ventricular hypertrophy.
with increased production of reactive oxygen speciesthat are known to compromise a variety of othercellular processes and to induce adverse cardiac re-modeling (68). However, a recent study raises doubtabout the role of DAG and ceramide as mediators oflipotoxic heart disease. Son et al. (69) assessed meta-bolic changes in a peroxisome proliferator-activatedreceptor-alpha– deficient model of peroxisomeproliferator-activated receptor-gamma–induced car-diolipotoxicity and reported increased rates of fattyacid oxidation with preserved cardiac function andimproved survival despite no changes in triglycerides,DAG, and ceramide levels. This now questions thebiological relevance of these lipotoxic intermediates inmediating contractile dysfunction.

Metabolic Remodeling in the Heart of Patients WithPre-Clinical and End-Stage Renal Disease

Whereas MI and ischemic heart disease account forthe significant portion of patients with heart failureand left ventricular remodeling, several sequelae ofrenal failure can also contribute to left ventricularmetabolic remodeling, termed uremic cardiomyopa-thy (70–72) (Fig. 5). Kidney disease affects over 19million American adults, and the prevalence ofmoderate-to-severe chronic kidney disease (CKD) in

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individuals who are not on dialysis is high (73). TheUnited States Renal Data System has reported near-equivalent rates of MI and cardiac death in dialysispatients and an approximately 10-fold higher rate ofheart failure in the same population (74). The com-mon occurrence of heart failure in the dialysis popu-lation is thought to be related to left ventricularhypertrophy that occurs frequently in patients withCKD. Hypertension is common among patients withrenal disease and has been suggested to be volume-dependent. Therefore, both volume- and pressure-overload would trigger left ventricular hypertrophy,whereas further changes in structure (e.g., anterior wallthickening and arterial stiffening) and hormone status(i.e., activation of neurohormones) take place. Concom-itantly, renal function declines and CKD progresses.

The so-called uremic cardiomyopathy probably hasmultiple causes. One of them involves a myocyte-capillary mismatch, with a diminished vascular supplyrelative to the number and volume of functioningmyocytes (75). As in the ischemic heart, the oxygen-poor milieu leads to a decline in aerobic myocardialfatty acid use and a shift to anaerobic glycolyticmetabolism, with increased uptake of glucose as theprincipal energy-providing substrate (76,77). The shiftfrom a predominance of aerobic (fatty acid) to anaer-obic (glucose) metabolism appears to account for asignificant portion of the excessive cardiovascularmorbidity and mortality observed across all stages ofkidney disease (70,78). Thus, the application of anoninvasive, quantitative PET technique to monitormyocardial metabolism in early-stage kidney disease hasthe potential to identify deleterious changes in cardiacmetabolism before its manifestation as contractile dys-function and cardiac hypertrophy.Pre-clinical myocardial metabolic alterations in CKD.18F-FDG PET images are usually interpreted quali-tatively in areas with myocardial perfusion deficits atrest and designated as either metabolism-perfusionmismatch (indicating viable myocardium) or match(indicating scarred myocardium) defects. However,detection of early, pre-clinical myocardial metabolicalterations can be limited with qualitative assessmentof regional 18F-FDG uptake. Although the distribu-tion of 18F-FDG uptake may visually appear homo-geneous throughout the left ventricular myocardium,absolute myocardial glucose use may be abnormal.Quantitative assessment with PET may identify alter-ations in whole myocardial glucose uptake (MGU)before clinical, functional, and prognostic conse-quences ensue.

The feasibility of employing quantitative MGU
with PET to gain additional insight into the altera- d
tions of myocardial metabolism in CKD patients wasrecently studied (77). The investigators demonstrateda significant inverse correlation between myocardialglucose uptake and renal function, assessed by esti-mated glomerular filtration rate, in CKD patients.The relationship between MGU and estimated glo-merular filtration rate could not be ascribed to demo-graphic factors or cardiac workload. Thus, 18F-FDG

ET may be an effective tool to investigate pre-clinicalhanges in myocardial metabolism in CKD.Myocardial metabolic alterations in end-stage CKD. In

emodialysis patients without coronary artery dis-ase, investigators have demonstrated alterations inyocardial fatty acid use in subsets of patients by

sing 123I-BMIPP SPECT. Reduced uptake of123I-BMIPP correlates with reduced left ventricularejection fraction and increased systemic insulinresistance (76). Whereas some studies have demon-strated that systemic insulin resistance is associatedwith heart failure and cardiac insulin resistance(79), others have argued that it does not (80). Theimportance of assessing metabolic changes in theheart of patients with end-stage CKD was, how-ever, underlined by another study where impaired123I-BMIPP uptake was shown to identify patientswith a high risk for cardiac death (78). The appli-cation of metabolic imaging with PET and SPECTtracers has the potential to offer useful insights intothe pathogenesis for uremic cardiomyopathy and topoint toward therapies for this disease. For exam-ple, carnitine deficiency is known to be common inend-stage renal disease and supplementation topatients on dialysis has been evaluated as a potentialtreatment for heart failure and hypotension (81). Atleast 1 study has used SPECT to examine the effectof carnitine supplementation on free fatty acidmetabolism in patients with end-stage renal disease(82). The study demonstrated enhanced washout ofmyocardial 123I-BMIPP with carnitine treatmentbut no change in the heart-to-mediastinal ratio.The relatively preserved heart-to-mediastinal 123I-

MIPP uptake in the chronic hemodialysis patientsuggests that the myocardial adenosine triphos-hate content in these patients (hence adenosineriphosphate– dependent conversion of 123I-MIPP to 123I-BMIPP coenzyme A) had notecreased in these patients despite carnitine defi-iency. As such, there was no accelerated back diffu-ion of the nonmetabolized radiotracer. However,ecause carnitine is essential for the transport ofong-chain fatty acids from the cytoplasm into the

atrix of mitochondria (the site of beta-oxidation),
ecreased carnitine availability results in longer resi-

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dence of free fatty acids in the cytoplasm (in the formof 123I-BMIPP coenzyme A), as reflected by the lowerwashout rate of the radiotracer before carnitine ad-ministration. These findings are supported by theexperimental observation in rats exhibiting prolongedretention of 123I-BMIPP in the myocardium whenpretreated with a mitochondrial carnitine acyltrans-ferase I inhibitor (83).

New Horizons

Metabolomics. Our current knowledge of the dy-amics of intermediary metabolism remains frag-ented and poorly integrated into the biology of

he cell. The new and powerful tools of systemsiology give a fresh approach to the diagnosis andreatment of different forms of heart disease. A casen point is the field of metabolomics. In analogy tohe genome, the transcriptome, and the proteome,he metabolome has been defined as the total set ofow molecular weight metabolites. The techniquesf metabolomics (in particular nuclear magneticesonance and mass spectroscopy) allow us to ana-yze changes in the metabolome in a given system.

major advantage of this metabolic profiling is theomparatively small number of possible targets: Theuman Metabolome Database currently lists ap-

roximately 7,900 small metabolites, comparedith 25,000 genes, 100,000 transcripts, and,000,000 proteins (84). Further, metabolites mayhow a better correlation with a disease’s phenotypehan messenger ribonucleic acids or proteins, ashey are further proximal reporters of a pathologicalrocess. Recent studies have delivered promisingesults and reported new markers for the develop-ent of type 2 diabetes (85) or coronary artery

isease and subsequent cardiovascular events (86).Considering our hypothesis of metabolic changes

receding and triggering structural and functionalhanges in the heart, metabolomics can be usefuleyond the mere exploration of biomarkers and canssist the search for mediators of cardiovasculariseases. However, the impact of changes in theetabolome is debated and additional mechanistic

tudies would be needed to define the biologicalelevance of such changes. Although the use ofetabolomics for assessing cardiovascular diseases

s still in its infancy, it may soon be a powerful tooln the quest for alterations in metabolite levels andetermining their pathophysiological impact.

Tracking the fate of transplanted stem cells. Myocar-ial regeneration through stem cell injection is a
eguiling concept, which to date has produced
ixed results. Laboratory experiments and clinicalrials suggest that cell-based therapies can improveardiac function (87). Several experimental strate-ies to “remuscularize” and revascularize the failingeart using adult stem cells or pluripotent stemells, cellular reprogramming, or tissue engineeringre in progress and offer unique opportunities foretabolic imaging.After MI, patients have a high risk of developing

eart failure due to cardiomyocyte death. Althoughhe current treatments of MI aim to reduce thextent of cell death in the heart, they cannot restoreyocardial contractility. With a cell-based therapy,yocytes can be generated out of adult, autolo-

ously transplanted stem cells and, therefore, pre-ent the progression into heart failure. Whereas theecent development in the field of stem cell therapys out of the scope of this review, it is appropriate toomment on using imaging techniques to trackransplanted stem cells in vivo. Although pre-linical studies have delivered promising data, con-erns about dose requirements, localization afternjection, as well as viability impede the clinical usef autologously transplanted stem cells. All of thesespects can be assessed with the help of noninvasivemaging techniques.

In general, stem cells can be tracked with differ-nt imaging methods such as cardiac magneticesonance imaging, PET, and SPECT. Further,ultimodality approaches, combining PET or

PECT with cardiac magnetic resonance imagingr computed tomography, merge the advantagesnd datasets delivered by each imaging techniquetself (88). Stem cells can be labeled with radioactive

arkers before transplantation to assess their local-zation in the host’s body. However, concerns abouthe dissociation of the radionuclide from the stemell have questioned the reliability of this techniqueor long-time studies, although it is a valid methodo determine the success of a transplantation di-ectly after delivery (88). Nonetheless, metabolicmaging of stem cells with 18F-FDG has producedromising results tracking the homing of cluster ofifferentiation CD34� cells to infarcted myocar-

dium (Fig. 6) (89). A different labeling techniqueuses reporter genes that are introduced into the stemcells or the host genome. Beside the ability to performlong-time studies, the use of reporter genes allows theinvestigator or clinician to assess stem cell survival, asonly viable cells produce the reporter probe. A recentstudy by Lee et al. (90) has demonstrated the appli-cability of these techniques in a large-animal model.
Briefly, the investigators generated induced pluripo-

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tent stem cells (iPSC) from adipose stromal cells in acanine model and transduced these iPSC with atriple-fusion reporter gene that included the herpessimplex truncated thymidine kinase. After injection of9-[4-[(18)F]fluoro-3(hydroxymethyl)butyl]guanine,they could determine the accumulation of iPSC (asincreased tracer activity) in the anterior wall andconfirm its localization by cardiac magnetic resonanceimaging and colabeling of iPSC with iron-oxideparticles. Improving stem cell targeting and reparativecapacity will also rely heavily on metabolic imagingwith PET in the future (91). Although the usefulnessof this strategy is beyond question, little work has beendone in this area until now.

Conclusions

In recent years, the tools of molecular and cellularbiology have provided new insights into the com-

Figure 6. Myocardial Homing and Biodistribution of 18F-FDG–La

Left posterior oblique (A) and left anterior oblique (B) views of che18F-FDG–labeled, unselected bone marrow cells (BMC) into left circuthe heart (infarct center and border zone), liver, and spleen. Left poupper abdomen of Patient #7 taken 70 min after transfer of 18F-FDrior descending coronary artery. Homing of CD34-enriched cells is dCD34� cell homing is most prominent in infarct border zone (arrowfrom Hofmann et al. (89). Abbreviation as in Figure 4.

plex mechanisms of metabolic pathways and the E

multitude of potential targets that can be exploredfor the treatment of various heart diseases. SPECTand PET imaging techniques provide a sensitive,noninvasive, quantitative tool for investigating pre-clinical and clinical abnormalities in myocardialperfusion, metabolism, enzymatic, or receptor de-rangements and allow for monitoring disease pro-gression and the effectiveness of medical therapy.The new fields of metabolomics and stem cellimaging offer challenges to both the experimentalbiologist and the clinical cardiologist to refine thetools of metabolic imaging for the diagnosis andtreatment of myocardial diseases.

Reprint requests and correspondence: Dr. Heinrich Tae-tmeyer, University of Texas Medical School at Houston,epartment of Internal Medicine, Division of Cardiol-

gy, 6431 Fannin, MSB 1.246, Houston, Texas 77030.

ed BMCs

d upper abdomen of Patient #2 taken 65 min after transfer ofex coronary artery. BMC homing is detectable in the lateral wall ofior oblique (C) and left anterior oblique (D) views of chest andbeled, cluster of differentiation CD34-enriched BMC into left ante-ctable in the anteroseptal wall of the heart, liver, and spleen.ds) but not infarct center (asterisk). Reprinted, with permission,

bel

st anmflsterG–laetehea

-mail: [email protected].

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Key Words: cardiac metabolism
y imaging y tracers.

targeted metabolic imaging to improve the management of heart

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