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Cardiovascular Molecular Imaging¹

¹ From the Department of Medicine, Division of Cardiology (J.C.W.), Department of Radiology, Molecular Imaging Program at Stanford (J.C.W., S.S.G.), and Bio-X Program (S.S.G.), Stanford University, 300 Pasteur Dr, Edwards Bldg R354, Stanford, CA 94305-5344; and Department of Nuclear Medicine, Johns Hopkins University, Baltimore, Md (F.M.B.). Received January 25, 2006; revision requested March 24; revision received April 7; final version accepted June 1. Address correspondence to J.C.W. (e-mail: joewu{at}stanford.edu).

	ABSTRACT

TOP ABSTRACT INTRODUCTION ATHEROSCLEROSIS MYOCARDIAL ISCHEMIA CORONARY ARTERY DISEASE MYOCARDIAL VIABILITY HEART FAILURE CARDIAC GENE THERAPY STEM CELL TRANSPLANTATION CONCLUSION References

 
The goal of this review is to highlight how molecular imaging will impact the management and improved understanding of the major cardiovascular diseases that have substantial clinical impact and research interest. These topics include atherosclerosis, myocardial ischemia, myocardial viability, heart failure, gene therapy, and stem cell transplantation. Traditional methods of evaluation for these diseases will be presented first, followed by methods that incorporate conventional and molecular imaging approaches.

© RSNA, 2007

	INTRODUCTION

TOP ABSTRACT INTRODUCTION ATHEROSCLEROSIS MYOCARDIAL ISCHEMIA CORONARY ARTERY DISEASE MYOCARDIAL VIABILITY HEART FAILURE CARDIAC GENE THERAPY STEM CELL TRANSPLANTATION CONCLUSION References

 
Molecular imaging is a rapidly advancing biomedical research and clinical discipline. Compared with traditional in vitro tissue culture and in vivo animal studies, molecular imaging allows noninvasive, quantitative, and repetitive imaging of targeted biological processes at both the cellular and subcellular levels within a living organism (1). This kind of imaging provides an extremely powerful technique with numerous applications, such as the monitoring of endogenous transcriptional regulation, analysis of gene transfer, tracking of tumor cell survival, screening for transgenic animal phenotypes, and expediting of drug discovery (2). Although the primary focus traditionally has been in the field of cancer biology, molecular imaging approaches have now been extended to several cardiovascular-related applications.

The goal of this review is to highlight how molecular imaging will impact the management and improved understanding of the major cardiovascular diseases that have substantial clinical impact and research interest. These topics include atherosclerosis, myocardial ischemia, myocardial viability, heart failure (HF), gene therapy, and stem cell transplantation. Traditional methods of evaluation for these diseases will be presented first, followed by methods that incorporate conventional and molecular imaging approaches. Conventional cardiovascular imaging focuses on obtaining anatomic, physiologic, or metabolic information and includes modalities such as echocardiography, magnetic resonance (MR) imaging, computed tomography (CT), single photon emission computed tomography (SPECT), and positron emission tomography (PET).

Although echocardiography, MR imaging, and CT typically are used to evaluate anatomic structures of the heart, they have limited capabilities in the assessment or visualization of physiologic and metabolic processes. Conversely, SPECT and PET can be used to evaluate physiologic and metabolic characteristics but are limited in their capability for visualization of anatomic structures. By using standard anatomic imaging modalities combined with molecular imaging technologies such as SPECT and PET, we now have the potential to detect disease processes at the anatomic, physiologic, metabolic, and molecular levels and, thereby, allow (a) earlier detection of diseases, (b) objective monitoring of therapies, and (c) better prognostication of disease progression (3).

	ATHEROSCLEROSIS

TOP ABSTRACT INTRODUCTION ATHEROSCLEROSIS MYOCARDIAL ISCHEMIA CORONARY ARTERY DISEASE MYOCARDIAL VIABILITY HEART FAILURE CARDIAC GENE THERAPY STEM CELL TRANSPLANTATION CONCLUSION References

 
Atherosclerosis is a dynamic multifactorial disease of the arterial wall. Although it generally involves the entire vascular system, cardiovascular manifestations are found most frequently and ultimately result in clinically overt coronary artery disease (CAD). A variety of factors contribute to development and progression of atherosclerosis. Dysfunction of the endothelium, which maintains vascular homeostasis by regulating vascular tone, smooth muscle cell proliferation, and thrombogenicity, is thought to be the earliest step in the development of CAD. The endothelial dysfunction results in the imbalance of vascular regulatory mechanisms to cause damage to the arterial wall (4). Inflammation, macrophage infiltration, lipid deposition, calcification, extracellular matrix digestion, oxidative stress, cell apoptosis, and thrombosis are among further molecular mechanisms that contribute to plaque development and progression (5) (Fig 1a, 1b).

View larger version (21K): [in this window] [in a new window] [Download PPT slide]   Figure 1a: From atherosclerotic plaque biology toward molecular plaque imaging. (a) Atherosclerosis and vascular structure. Image shows development of expansive vascular remodeling, which may result in substantially increased vulnerability without luminal narrowing. Ultimately, changes lead to acute plaque rupture or to chronic stenosis with luminal narrowing (right). (b) Criteria of plaque vulnerability as targets for imaging. Image depicts morphologic and biologic features of vulnerable plaques, which are suitable targets for imaging approaches. (c) Future perspective in regard to multimodality imaging of plaque morphology and biology. Image highlights the potential of hybrid imaging technologies, which may allow noninvasive fusion of morphology from angiography with biology from nuclear imaging of plaque-targeted molecular probes (nuclear and fusion images are simulated).

View larger version (20K): [in this window] [in a new window] [Download PPT slide]   Figure 1b: From atherosclerotic plaque biology toward molecular plaque imaging. (a) Atherosclerosis and vascular structure. Image shows development of expansive vascular remodeling, which may result in substantially increased vulnerability without luminal narrowing. Ultimately, changes lead to acute plaque rupture or to chronic stenosis with luminal narrowing (right). (b) Criteria of plaque vulnerability as targets for imaging. Image depicts morphologic and biologic features of vulnerable plaques, which are suitable targets for imaging approaches. (c) Future perspective in regard to multimodality imaging of plaque morphology and biology. Image highlights the potential of hybrid imaging technologies, which may allow noninvasive fusion of morphology from angiography with biology from nuclear imaging of plaque-targeted molecular probes (nuclear and fusion images are simulated).

View larger version (44K): [in this window] [in a new window] [Download PPT slide]   Figure 1c: From atherosclerotic plaque biology toward molecular plaque imaging. (a) Atherosclerosis and vascular structure. Image shows development of expansive vascular remodeling, which may result in substantially increased vulnerability without luminal narrowing. Ultimately, changes lead to acute plaque rupture or to chronic stenosis with luminal narrowing (right). (b) Criteria of plaque vulnerability as targets for imaging. Image depicts morphologic and biologic features of vulnerable plaques, which are suitable targets for imaging approaches. (c) Future perspective in regard to multimodality imaging of plaque morphology and biology. Image highlights the potential of hybrid imaging technologies, which may allow noninvasive fusion of morphology from angiography with biology from nuclear imaging of plaque-targeted molecular probes (nuclear and fusion images are simulated).

Although angiography still serves as a key test in the management of symptomatic CAD, several clinical observations have emphasized the need for a more detailed analysis of the structure and biology of atherosclerotic plaques. First, epidemiologic observations have shown that a large proportion of people who suffer a sudden cardiac event (acute ischemic syndrome or sudden cardiac death) have no prior symptoms (7). Second, it has been found that acute coronary syndromes often result from plaque rupture at sites with no or only modest luminal narrowing at angiography (8) (Fig 1a). Vascular remodeling, which consists of atherosclerosis-associated morphologic and biologic changes of the vessel wall without substantial stenosis, often has occurred at such sites (9). Therefore, there is considerable demand for diagnostic procedures that go beyond assessment of the vessel lumen to identify rupture-prone vulnerable plaques as the most frequent cause of sudden cardiac events (5).

As a consequence, several methods have been developed in recent years to provide detailed information about vessel wall and plaque morphology. Intravascular ultrasonography (US) is an invasive technique that allows assessment of vessel wall thickness and structure (10). In addition, optical coherence tomography has been introduced as another invasive technique that provides images of vessel wall morphology at almost histologic quality (11). Finally, MR imaging approaches also have been developed, and these approaches allow noninvasive characterization of the vessel wall (12). Some studies have shown that CT angiography allows additional assessment of plaque attenuation (13). The goal of these techniques is to identify vascular remodeling and describe plaques with regard to specific criteria of vulnerability, such as a thin fibrous cap and a large lipid core.

At least as important as its morphology, however, is the biology of a plaque (Fig 1b). Inflammation is a key feature of active, rupture-prone plaques, which can be identified invasively by using thermography (14). Plaque inflammation also may be identified noninvasively by using nuclear imaging with fluorine 18 (¹⁸F) fluorodeoxyglucose (FDG) or other markers of inflammatory activity (15). Further molecular features of unstable plaques, which have been targeted by specific probes, are macrophage infiltration (16,17), proliferating smooth muscle cells (18), matrix metalloproteinase activation (19), apoptosis of macrophages and smooth muscle cells (20,21), oxidative stress (22), and proangiogenetic factors (23) (Table 1).

	MYOCARDIAL ISCHEMIA

TOP ABSTRACT INTRODUCTION ATHEROSCLEROSIS MYOCARDIAL ISCHEMIA CORONARY ARTERY DISEASE MYOCARDIAL VIABILITY HEART FAILURE CARDIAC GENE THERAPY STEM CELL TRANSPLANTATION CONCLUSION References

 
As mentioned previously, atherosclerosis ultimately progresses to clinically overt CAD. In the treatment of clinical CAD, a paradigm change has occurred in recent years. It is increasingly emphasized that the decision for invasive work-up and intervention cannot be based on symptoms and morphologic detection of coronary stenoses alone. Functional tests allow accurate identification of the presence, extent, and severity of myocardial ischemia, which is closely correlated to patient outcome. At present, detection of myocardial ischemia thus serves as a gatekeeper to coronary angiography and guides the clinician to choose interventional or medical therapy on the basis of individual cardiovascular risk (Fig 2).

View larger version (29K): [in this window] [in a new window] [Download PPT slide]   Figure 2a: Imaging in myocardial ischemia. (a) Imaging markers in CAD. (b) Examples of morphologic, functional, and molecular images. LAD = left anterior descending artery, LCA = left coronary artery, LCX = left circumflex artery, RCA = right coronary artery.

View larger version (27K): [in this window] [in a new window] [Download PPT slide]   Figure 2b: Imaging in myocardial ischemia. (a) Imaging markers in CAD. (b) Examples of morphologic, functional, and molecular images. LAD = left anterior descending artery, LCA = left coronary artery, LCX = left circumflex artery, RCA = right coronary artery.

Nonnuclear imaging techniques for detection of myocardial ischemia are becoming increasingly available. These techniques have the advantage of no radiation exposure, but their diagnostic and prognostic usefulness is still less well established compared with perfusion scintigraphy. Echocardiography can be applied for detection of wall motion abnormalities during physical exercise (31) or dobutamine stimulation (32). Furthermore, contrast-enhanced echocardiography has been established for measuring perfusion with echogenic microbubbles (33). A promising approach to detection of ischemia is MR imaging. This technique is thought to be less dependent on patient conditions and observer experience. MR imaging can be effectively used for detection of ischemia-associated wall motion abnormalities during dobutamine stimulation (34) or for direct assessment of myocardial perfusion after a bolus injection of a gadolinium-based contrast agent at rest and during pharmacologic vasodilation (35). Although these nonnuclear methods are likely to grow in the future, it is thought that nuclear imaging will be pushed by the hybrid PET/CT and SPECT/CT cameras, which allow further refinement of functional cardiac assessment with measurement of myocardial perfusion, geometry, function, and coronary morphology within a single imaging session.

Assessment of ischemia by using measurement of perfusion and function will remain the method for stratification of patients with known CAD. Identification of ischemia-associated molecular alterations, however, may find a role in certain situations that are not yet possible through conventional assessment of perfusion and/or contractile function. Specific identification of myocardium that has previously been exposed to ischemia, but is now normally perfused, would be of considerable interest. An ischemic memory marker would allow identification of myocardium at risk in patients with acute coronary syndromes or extensive CAD. It may also provide insights into the clinical role of ischemic preconditioning, a cellular mechanism by which short episodes of ischemia and reperfusion result in an improved tolerance of prolonged ischemic episodes (36).

Annexin V is a protein that can be radiolabeled and that binds to phosphatidylserine, a molecule expressed on the cell surface during the early phase of apoptosis (programmed cell death). Recent studies have shown that annexin V uptake occurs not only in irreversibly damaged infarcted myocardium (37) but also temporarily in myocardium after reversible severe ischemia (38,39). These observations suggest that early phases of apoptosis are reversible and that annexin V may be used as a molecular marker to identify areas that have previously suffered severe ischemia but have not yet transformed to scar. Another approach for molecular imaging of ischemic memory is the application of the radiolabeled fatty acid analogue iodine 123 (¹²³I) ß-methyl-p-iodophenyl-pentadecanoic acid. After episodes of ischemia, which result in a metabolic shift from fatty acids to glucose as the preferred substrate for energy production, regional uptake of this tracer seems to be reduced for a longer period of time (40).

	CORONARY ARTERY DISEASE

TOP ABSTRACT INTRODUCTION ATHEROSCLEROSIS MYOCARDIAL ISCHEMIA CORONARY ARTERY DISEASE MYOCARDIAL VIABILITY HEART FAILURE CARDIAC GENE THERAPY STEM CELL TRANSPLANTATION CONCLUSION References

 
Another area of interest for targeted molecular imaging is to identify patients with CAD who have a high likelihood for ischemia-induced remodeling, a phenomenon that results in transition to HF. Early identification of such patients would allow prevention of the development of remodeling-associated ventricular dilatation and reduction of contractile function. Alterations of the cardiac sympathetic nervous system seem to play a critical role in left ventricular remodeling. Integrity of presynaptic sympathetic nerve endings can be identified by using radiolabeled catecholamines such as ¹²³I–m-iodobenzylguanidine (MIBG). Researchers in several studies have identified innervation defects larger than perfusion defects in patients with CAD and after MI; these findings suggest that sympathetic neurons are more sensitive to ischemia than are myocytes (41,42).

An imbalance of autonomic signal transduction may contribute to the maladaptive process of postischemic remodeling. This idea has been suggested by investigators who observed accelerated ventricular dilatation in patients with larger innervation defects that were indicated by reduced myocardial MIBG uptake (43). In addition to presynaptic innervation, postsynaptic receptor density can be evaluated by using PET and radiolabeled adrenergic receptor antagonists. Findings in a study showed that reduction of ß-adrenergic density early after MI can be used to predict ventricular volumes at 6 months after the event (44); such results suggest that receptor-targeted imaging may be another approach to identify candidates for remodeling. Other molecular targets in the ischemic myocardium include integrins, a group of adhesion molecules that play a central role in angiogenesis. These can be identified with specific vß3-integrin–targeted radiotracers in vivo (45) and may allow assessment of postischemic recovery and angiogenesis therapy in the future (46). Finally, myocyte apoptosis is thought to be another relevant feature of remodeling that may be targeted by noninvasive molecular imaging although no detailed trials have been performed up to now.

	MYOCARDIAL VIABILITY

TOP ABSTRACT INTRODUCTION ATHEROSCLEROSIS MYOCARDIAL ISCHEMIA CORONARY ARTERY DISEASE MYOCARDIAL VIABILITY HEART FAILURE CARDIAC GENE THERAPY STEM CELL TRANSPLANTATION CONCLUSION References

 
It has been extensively documented that patients with poor left ventricular function and advanced multivessel CAD show improved clinical outcome after surgical revascularization (47–50). These patients may benefit most from revascularization, but the decision to proceed with interventional therapy is not an inconsequential one. Patients with severe ventricular dysfunction undergo coronary artery bypass graft surgery or percutaneous coronary intervention with a considerable risk of procedure-related morbidity and mortality (50). Hence, accurate methods to identify patients who will benefit most are required to justify the potential risks.

There has been increasing clinical awareness that contractile dysfunction in patients with CAD does not necessarily reflect the presence of scar tissue (51). In investigations of contractile reserve in the catheterization laboratory in the 1970s, reversibility of left ventricular dysfunction was described (52,53). Since then, several noninvasive imaging techniques have been developed to identify tissue viability in dysfunctional myocardium and to thereby determine which patients with ventricular dysfunction are the most appropriate candidates for revascularization (54).

Two major pathogenetic mechanisms, which coexist in most clinical situations, contribute to development of dysfunctional but still viable myocardium. First, "myocardial stunning" describes a state of persistent postischemic contractile dysfunction despite restoration of near-normal blood flow. In addition to "acute stunning" that occurs as a consequence of a single episode of ischemia, the definition of myocardial stunning has been extended to chronic left ventricular dysfunction associated with repetitive episodes of ischemia, which is then referred to as "repetitive stunning" (55). Molecular mechanisms for stunning include intracellular calcium overload caused by ischemia, which results in desensitization and lysis of myofilaments (56), and generation of oxygen-derived free radicals, which inhibit ionic pumps and mitochondrial function, at reperfusion (57).

Second, "myocardial hibernation" has been described as a consequence of reduced resting perfusion caused by severe coronary stenosis that leads to an adaptive downregulation of contractile function, which is reversible after reestablishment of normal perfusion (51,58). Uncoupling of contractile work and myocardial blood flow is thought to be part of this adaptation. Since approximately 60% of oxygen consumption is linked to contractile performance, energy can be saved and the tolerance to ischemia can be increased at the expense of regional dysfunction. It has been shown that this adaptive process is associated with molecular alterations, such as dedifferentiation of myocytes, decreased expression of contractile proteins, accumulation of glycogen, loss of sarcoplasmic reticulum, small mitochondria, and increasing interstitial fibrosis (59–61).

The prediction of functional recovery by using detection of myocardial viability has emerged as a clinical application for molecular imaging. Reversible left ventricular dysfunction is generally associated with maintained or even increased tissue uptake of the glucose metabolic marker FDG (62–64). Hibernating and repetitively stunned myocardia are characterized by a perfusion-metabolism mismatch pattern with reduced regional uptake of a perfusion tracer but preserved uptake of FDG metabolic tracer. Scar tissue, on the other hand, is characterized by a matched reduction of perfusion and FDG uptake (Fig 3). Studies of myocardial metabolism by using FDG and PET have provided important information for a better understanding of the pathophysiologic interrelations among myocardial blood flow, substrate metabolism, and contractile function in ischemically compromised myocardium. These studies have also played a fundamental role in the clinical emergence of noninvasive viability imaging and are regarded as an imaging reference standard (65,66). An extensive body of literature exists that documents the diagnostic accuracy of FDG PET for prediction of functional recovery after revascularization. In addition, the prognostic value of PET has been described (67,68), and the perfusion-metabolism mismatch has been identified as an unstable state associated with a high risk and poor outcome if not treated immediately (69,70).

View larger version (51K): [in this window] [in a new window] [Download PPT slide]   Figure 3: Examples of patterns of myocardial viability from perfusion-metabolism PET imaging. Representative left ventricular (LV) short- and long-axis sections from two patients with severe ventricular dysfunction are depicted in "hot metal" color scale (brighter color indicates higher radioactivity concentration). In top two rows, an anteroseptal perfusion defect is present in [13N]–NH3 perfusion images, with concomitant matched reduction of uptake of the metabolic tracer FDG. This pattern indicates the presence of scar tissue, which will not benefit from revascularization. In bottom two rows, a perfusion defect is shown in the anterior and apical wall. Enhanced FDG uptake is found in the metabolic study, indicating the presence of ischemically compromised hibernating myoardium, which will benefit from revascularization. Note that relatively reduced uptake of FDG in normally perfused inferior wall is consistent with use of fatty acids as substrate in this area of normally perfused myocardium. LA = left atrium, RA = right atrium, RV = right ventricle.

Further, MR imaging has been used to identify scar tissue by means of the retention of gadolinium-based contrast agent. Imaging of gadolinium-based contrast agent late enhancement allows accurate detection of the regional and transmural extent of irreversibly damaged myocardium. It has been shown that the transmural extent of gadolinium-based contrast agent enhancement is correlated with the likelihood of regional functional recovery (74). The diagnostic and prognostic accuracy of this test, however, needs to be defined in detail. Findings in other studies have suggested that functional measures of regional viability may be superior to the static measurement of the extent of necrotic tissue for prediction of recovery (75) and, thus, that biologic and molecular mechanisms other than scar development are important in chronic ischemic ventricular dysfunction.

Innovations in molecular imaging may allow refinement of the characterization of jeopardized myocardium and, thus, further improvement of diagnostic and prognostic assessment of myocardial viability in the future. The extent of apoptotic cell death in hibernating myocardium may be identified by using tracers such as radiolabeled annexin V. This may allow one to identify the severity of ischemic damage and the transition from programmed cell survival to programmed cell death. Other biologic targets for molecular imaging in chronic dysfunctional myocardium may be extracellular matrix activation, collagen deposition, or inflammation. Finally, multimodality imaging may be of special value in chronic left ventricular dysfunction by providing a combination of morphologic, functional, and metabolic information (Fig 4).

View larger version (72K): [in this window] [in a new window] [Download PPT slide]   Figure 4: Multimodality imaging of myocardial viability. Short-axis MR images show late enhancement of gadopentetate dimeglumine (in gray scale) and PET images show glucose metabolism (using FDG) and perfusion (using [13N]–NH3[NH3]). PET images are displayed in a hot metal color scale where brighter color indicates higher radioactivity concentration. Nontransmural late enhancement, indicating subendocardial scar tissue, is shown on MR images. PET scans show reduced perfusion in the same area (bottom middle), but FDG uptake is less reduced and higher compared with perfusion (top middle). This perfusion-metabolism mismatch indicates residual viability in the subepicardial portion of the area with subendocardial scar. IR TrueFISP +Gd = inversion-recovery true fast imaging with steady-state precession and gadolinium-based contrast agent.

	HEART FAILURE

TOP ABSTRACT INTRODUCTION ATHEROSCLEROSIS MYOCARDIAL ISCHEMIA CORONARY ARTERY DISEASE MYOCARDIAL VIABILITY HEART FAILURE CARDIAC GENE THERAPY STEM CELL TRANSPLANTATION CONCLUSION References

It is known that approximately 50% of all HF deaths are caused by ventricular tachycardia and approximately 80% of patients with symptomatic systolic dysfunction have ventricular tachycardia (80). Results of the Multicenter Automatic Defibrillator Implantation Trial (also known as MADIT-II) showed that routine implantation of ICDs in patients with a prior MI and an ejection fraction of less than 30% led to reduction of mortality rates from 19.8% (conventional therapy group) to 14.2% (ICD group) (hazard ratio = 0.69, P = .16) (81). Findings in this study suggested that ICD implantation should be considered routinely in all patients with reduced ventricular ejection fraction after MI (82). Besides risk of sudden cardiac death, patients with HF can have intraventricular dyssynchrony (or left bundle branch block), which causes the two ventricles to beat in an asynchronous fashion, reduces systolic function, and increases systolic volume.

Intraventricular dyssynchrony is seen in approximately 15%–30% of patients with HF (83). Cardiac resynchronization therapy paces both the right and left ventricle, which can synchronize the activation of the heart and, thus, improve left ventricular systolic function (84). This differs from the typical pacemaker, which paces only the right ventricle. In the Multicenter InSync Randomized Clinical Evaluation (also called MIRACLE), results indicated that cardiac resynchronization therapy improved symptoms, exercise tolerance, and quality of life substantially (84). However, the estimated cost of cardiac resynchronization therapy and/or ICD and hospitalization for implantation is between $40 000 and $50 000 per patient (78). Applying this expense to the estimated 400 000 to 1.5 million patients with HF who may benefit from ICD poses an astronomic burden to health care costs. In addition, an estimated 20%–30% of patients do not respond to cardiac resynchronization therapy (85). Thus, these issues emphasize the need for additional measures that can be used to selectively identify which patients will benefit the most from ICD and cardiac resynchronization therapy.

Traditionally, the single most useful diagnostic test for the evaluation of patients with HF is two-dimensional echocardiography coupled with a Doppler flow study. Echocardiography can provide global and regional function, degree of ventricular remodeling, contractile reserve, ischemia, and viability, particularly in patients after acute coronary syndromes or patients with chronic HF. However, these measurements do not address the issue of intraventricular conduction delays. Newer echocardiographic measurements, which include tissue Doppler imaging (86), strain rate imaging (87), and tissue tracking (88), have all been advocated. These parameters may provide optimal information on intraventricular dyssynchrony and allow prospective identification of responders to cardiac resynchronization therapy (89). A detailed discussion of each modality is beyond the scope of this review, but interested readers should refer to published articles (89,90).

Investigators in several studies have also demonstrated that ¹²³I-MIBG imaging can provide powerful diagnostic and prognostic information in patients with HF. Many radiotracers for scintigraphic imaging of cardiac neurotransmission have been developed with radiolabeling of the neurotransmitters or their structural analogs (Fig 5a). Of these, MIBG shares many cellular uptake and storage properties with norepinephrine, and, thus, MIBG scans have been used to evaluate cardiac sympathetic nervous system distribution and function. In patients with HF, MIBG scans typically show a reduced heart-mediastinum uptake ratio, heterogeneous distribution within the myocardium, and increased MIBG washout from the heart (91–93) (Fig 5b, 5c). For example, Arimoto et al (94) showed that patients with abnormally rapid washout levels had a significantly higher cardiac event rate than did those with normal washout levels (57% vs 12%, P < .0001) during the follow-up period (6–30 months).

View larger version (39K): [in this window] [in a new window] [Download PPT slide]   Figure 5a: 123I-MIBG imaging in patients with HF. (a) Schematic shows most commonly used radioligands for assessment of cardiac pre- and postsynaptic processes. (b) SPECT MIBG study in healthy volunteer. Short-axis tomograms and reconstructed polar maps show normal MIBG distribution and washout. (c) SPECT MIBG study in patient with dilated cardiomyopathy. Short-axis tomograms and reconstructed polar maps show decreased and heterogeneous myocardial MIBG activity. ATP = adenosine triphosphate, DOPA = dihydroxyphenylalanine, cAMP = cyclic adenosine monophosphate, NE = norepinephrine. (Reprinted, with permission, from reference 91.)

View larger version (63K): [in this window] [in a new window] [Download PPT slide]   Figure 5b: 123I-MIBG imaging in patients with HF. (a) Schematic shows most commonly used radioligands for assessment of cardiac pre- and postsynaptic processes. (b) SPECT MIBG study in healthy volunteer. Short-axis tomograms and reconstructed polar maps show normal MIBG distribution and washout. (c) SPECT MIBG study in patient with dilated cardiomyopathy. Short-axis tomograms and reconstructed polar maps show decreased and heterogeneous myocardial MIBG activity. ATP = adenosine triphosphate, DOPA = dihydroxyphenylalanine, cAMP = cyclic adenosine monophosphate, NE = norepinephrine. (Reprinted, with permission, from reference 91.)

View larger version (56K): [in this window] [in a new window] [Download PPT slide]   Figure 5c: 123I-MIBG imaging in patients with HF. (a) Schematic shows most commonly used radioligands for assessment of cardiac pre- and postsynaptic processes. (b) SPECT MIBG study in healthy volunteer. Short-axis tomograms and reconstructed polar maps show normal MIBG distribution and washout. (c) SPECT MIBG study in patient with dilated cardiomyopathy. Short-axis tomograms and reconstructed polar maps show decreased and heterogeneous myocardial MIBG activity. ATP = adenosine triphosphate, DOPA = dihydroxyphenylalanine, cAMP = cyclic adenosine monophosphate, NE = norepinephrine. (Reprinted, with permission, from reference 91.)

	CARDIAC GENE THERAPY

TOP ABSTRACT INTRODUCTION ATHEROSCLEROSIS MYOCARDIAL ISCHEMIA CORONARY ARTERY DISEASE MYOCARDIAL VIABILITY HEART FAILURE CARDIAC GENE THERAPY STEM CELL TRANSPLANTATION CONCLUSION References

 
Gene transfer has been heralded as the most promising therapy of molecular medicine in the 21st century. It is usually defined as the transfer and expression of DNA to somatic cells in an individual, with a resulting therapeutic effect. In cardiovascular diseases, gene therapy offers an exciting new approach to express the therapeutic factors locally in the myocardium (97). In general, the successful application of gene therapy requires three essential elements: (a) a vector for gene delivery, (b) delivery of the vector to the target tissue, and (c) a therapeutic gene to be expressed in a particular patient population.

An ideal vector should enable efficient gene delivery to the target tissue, have minimal local or systemic toxicity, deliver enough concentration and duration to induce a therapeutic effect, and cause no germ-line transmission to the offspring. No single vector has all of these attributes, and, therefore, the type of vector chosen will need to be tailored to the specific clinical applications. Vectors can be classified as viral vectors and nonviral vectors. Common viral vectors include adenovirus, adenoassociated virus, gutless adenovirus, and lentivirus. Nonviral vectors include plasmids, naked DNA, and liposomes (98). The technique of vector delivery to the heart also depends on the intended target area but in general can be categorized as the following: (a) direct epicardial injection, (b) endocardial injection, (c) intracoronary infusion, (d) retrograde coronary sinus infusion, and (e) pericardial injection (99).

Likewise, the choice of a therapeutic gene to be expressed is often driven by the intended application. In animal studies, successful gene therapy has been demonstrated for the following: (a) the treatment of CAD by using angiogenic factors such as vascular endothelial growth factor (VEGF) (100), fibroblast growth factor (101), and hypoxia-inducible factor 1 (102); (b) reduction of restenosis after angioplasty through inhibition of smooth muscle cell proliferation with suicide gene therapy by using thymidine kinase (103); (c) improvement of congestive HF with gene transfer of a calcium adenosine triphosphatase pump (SERCA2a) (104); (d) inhibition of atherosclerosis with overexpression of an high-density lipoprotein receptor (105); and (e) reduction of hypoxia-induced apoptosis of cardiomyocytes (106).

These encouraging results led to the initiation of several clinical trials beginning in the 1990s. Of the 509 ongoing gene therapy trials in the United States, 46 are related to cardiovascular diseases (107). The majority of these studies are aimed at testing the safety and efficacy of therapeutic angiogenesis and, to a lesser extent, examining restenosis. In the late 1990s, results of several phase 1 open-labeled trials that involved small numbers of patients with myocardial ischemia and peripheral vascular disease were uniformly positive (108–110). However, phase 2 randomized, double-blind, placebo-controlled trials have yielded conflicting, if not disappointing, results. In the Vascular Endothelial Growth Factor in Ischemia for Vascular Angiogenesis (also known as VIVA) (111), FGF Initiating Revascularization Trial (also called FIRST) (112), Adenovirus Fibroblast Growth Factor Angiogenic Gene Therapy (also known as AGENT) (113,114), and the Kuopio Angiogenesis Trial (also called KAT) (115), gene therapy was tested by using either vascular endothelial growth factor (VEGF) or fibroblast growth factor. Unfortunately, these trials failed to show any consistent improvement in various parameters, such as symptoms, ejection fraction, wall motion scores, myocardial perfusion, and restenosis rate.

Nonetheless, important lessons can be learned from these trials. They showed that angiogenesis is a complex process regulated by the interaction of various growth factors and may be difficult to stimulate by using a single protein or gene injection. The ideal injection method, delivery vector, and patient population remain to be determined. The pharmacokinetics and pharmacodynamics of therapeutic gene expression will need to be defined first before gene therapy can proceed further to widespread clinical use, and this process is similar to that for the research and development of experimental drugs. Finally, since there is no available method of assessing gene expression in vivo, investigators are unable to determine whether the lack of symptomatic improvement is due to poor injection technique, insufficient gene expression, the host inflammatory response, or an inappropriate therapeutic gene (116).

Most molecular imaging studies have focused on cancer biology (117, 118). Imaging of cardiac transgene expression was established in several proof-of-principle studies that involved the injection of various reporter genes into the myocardium and in which the kinetics of transgene expression was followed over time by using optical bioluminescence, micro-PET, and clinical PET imaging (119–123). The concept of imaging reporter gene expression (Fig 6) involves a reporter gene first being introduced into target tissues by various methods, which include viral and nonviral vectors. The upstream promoter that regulates the transcription of the reporter gene can be constitutive (always on), inducible (can be turned on or off), or tissue specific (expressed only in the tissues of interest).

View larger version (69K): [in this window] [in a new window] [Download PPT slide]   Figure 6: Four strategies of imaging reporter gene and reporter probe. A, Enzyme-based bioluminescence imaging. Expression of the firefly luciferase reporter gene leads to the firefly luciferase reporter enzyme, which catalyzes the reporter probe (D-luciferin) that results in a photochemical reaction. This yields low levels of photons that can be detected and quantified by a charge-coupled device camera. B, Enzyme-based PET imaging. Expression of the herpes simplex virus type 1 thymidine kinase (HSV1-tk) reporter gene leads to the thymidine kinase reporter enzyme, HSV1-TK, which phosphorylates and traps the PET reporter probe 9-(4-[18F]fluoro-3-hydroxymethylbutyl)guanine (FHBG) intracellularly. Radioactive decay of 18F isotopes can be detected with PET. C, Receptor-based PET imaging. 3-(2-[18F]fluoroethyl)spiperone (18FESP) is a reporter probe that interacts with the dopamine 2 receptor (D2R) to result in probe trapping on or in cells expressing the D2R gene. D, Receptor-based MR imaging. Overexpression of engineered transferrin receptor (TfR) results in increased cell uptake of the transferrin-monocrystalline iron oxide nanoparticles. These changes result in a detectable contrast change on MR image. FPCV = 8-[18F]fluoropenciclovir, holo-Tf = holo-transferrin. (Reprinted, with permission, from reference 98.)

The feasibility of linking a PET reporter gene to a therapeutic gene was demonstrated in two separate studies (124,125). In this case, an adenovirus containing two constitutive cytomegalovirus (CMV) promoters driving a VEGF₁₂₁ therapeutic gene and an HSV1-sr39tk PET reporter gene separated by poly-adenine sequences was constructed (Ad-CMV-VEGF₁₂₁-CMV-HSV1-sr39tk) (Fig 7a). Wu et al injected the construct into the myocardium of a rat in an MI model. Reporter gene expression, which indirectly reflects the VEGF₁₂₁ therapeutic gene expression, persisted for only approximately 2 weeks because of host immune response against the adenovirus (124). At 2 months, there was no substantial improvement in myocardial contractility, perfusion, or metabolism as measured by using echocardiography, ¹³N ammonia ([¹³N]–NH₃) perfusion, and FDG imaging between study and control groups (Fig 7b). Thus, this study highlights the importance of monitoring the pharmacokinetics of gene expression. It also demonstrates the proof of principle that any other cardiac therapeutic genes of interest (eg, hypoxia-inducible factor 1, sarcoplasmic endoplasmic reticulum Ca²⁺, heat shock protein, or endothelial nitric oxide synthase) can likewise be coupled to a PET reporter gene for subsequent noninvasive monitoring.

View larger version (52K): [in this window] [in a new window] [Download PPT slide]   Figure 7a: Molecular imaging of cardiac perfusion, metabolism, and gene expression. (a) Schematic of Ad-CMV-VEGF121-CMV-HSV1-sr39tk mediated gene expression. The translated product of VEGF121 is soluble and excreted extracellularly, whereas the translated product of HSV1-sr39tk (HSV1-sr39TK) traps FHBG intracellularly by phosphorylation. PCMV = CMV promoter. (b) At day 2, representative images showing normal perfusion ([13N]–NH3) and metabolism (FDG) in a sham rat, anterolateral infarction in a control rat, and anterolateral infarction in a study rat (Ad-CMV-VEGF121-CMV-HSV1-sr39tk) in short, vertical, and horizontal axis (gray scale). The color scale is expressed as percentage injected dose per gram (%ID/g) for FHBG uptake. Only the study rat showed robust HSV1-sr39tk reporter gene activity near the site of injection. (Reprinted, with permission, from reference 124.)

View larger version (20K): [in this window] [in a new window] [Download PPT slide]   Figure 7b: Molecular imaging of cardiac perfusion, metabolism, and gene expression. (a) Schematic of Ad-CMV-VEGF121-CMV-HSV1-sr39tk mediated gene expression. The translated product of VEGF121 is soluble and excreted extracellularly, whereas the translated product of HSV1-sr39tk (HSV1-sr39TK) traps FHBG intracellularly by phosphorylation. PCMV = CMV promoter. (b) At day 2, representative images showing normal perfusion ([13N]–NH3) and metabolism (FDG) in a sham rat, anterolateral infarction in a control rat, and anterolateral infarction in a study rat (Ad-CMV-VEGF121-CMV-HSV1-sr39tk) in short, vertical, and horizontal axis (gray scale). The color scale is expressed as percentage injected dose per gram (%ID/g) for FHBG uptake. Only the study rat showed robust HSV1-sr39tk reporter gene activity near the site of injection. (Reprinted, with permission, from reference 124.)

	STEM CELL TRANSPLANTATION

TOP ABSTRACT INTRODUCTION ATHEROSCLEROSIS MYOCARDIAL ISCHEMIA CORONARY ARTERY DISEASE MYOCARDIAL VIABILITY HEART FAILURE CARDIAC GENE THERAPY STEM CELL TRANSPLANTATION CONCLUSION References

 
In an acute MI, tissue loss leads to hemodynamic stress followed by compensatory left ventricular hypertrophy and dilatation. Many patients continue to develop refractory HF symptoms and require more aggressive approaches, such as a left ventricular assist device and orthotopic heart transplantation. However, the limitations of these approaches (eg, infection and bleeding for left ventricular assist device and organ shortage and graft rejection for orthotopic heart transplantation) justify the search for alternative therapeutic options.

Stem cell transplantation holds potential promise for treatment of ischemic heart disease. Orlic et al (128) reported transdifferentiation of bone marrow–derived hematopoietic stem cells into cardiomyocytes after myocardial injury in mice. However, researchers in subsequent studies have questioned the concept of differentiation across tissue lineage boundaries (129,130). Regardless, several phase 1 clinical trials involving transplantation of bone marrow stem cells, skeletal myoblasts, and endothelial progenitor cells have been initiated since then (131–138). Assmus et al (132) showed that transplantation of progenitor cells was associated with a substantial increase in global left ventricular ejection fraction, improved regional wall motion in the infarct zone, and reduced end-systolic left ventricular volumes at 4-month follow-up (Fig 8).

View larger version (57K): [in this window] [in a new window] [Download PPT slide]   Figure 8: Functional imaging studies in a patient after MI who underwent intracoronary infusion of circulating blood–derived progenitor cells. A, Left ventricular angiograms before circulating blood–derived progenitor cell therapy and, B, at 4-month follow-up. C, Pretherapeutic and, D, posttherapeutic corresponding FDG PET bull's-eye views of the left ventricle of the patient. LAD = left anterior descending artery, LCX = left circumflex artery, RCA = right coronary artery. (Reprinted, with permission, from reference 132.)

One of the main limitations of cardiac stem cell transplantation is the lack of available methods to assess stem cell survival. In clinical studies, changes in myocardial perfusion, viability, and perfusion are assessed with echocardiography, nuclear SPECT and PET imaging, or MR imaging (Table 2). These parameters can be used to measure the therapeutic effects but not to actually detect the presence or absence of transplanted stem cells. This is an important distinction because most patients also undergo concurrent coronary artery bypass graft or percutaneous coronary intervention, and it is not clear whether the improvement is due to these procedures or to the transplanted stem cells. Likewise, in animal studies, analysis of stem cell survival is based on postmortem histologic examination, which is invasive and precludes longitudinal monitoring (128–130,140). Thus, the ability to study stem cells in the context of the intact whole-body system rather than with indirect (clinical trials) or invasive (animal studies) means will give better insight into the underlying biology and physiology of stem cells. Several investigators have started addressing this issue through different approaches, including radionuclide labeling, ferromagnetic labeling, and reporter gene labeling (Table 3).

For reporter gene labeling, the cells are transfected with reporter genes prior to implantation into the myocardium. If the cells are alive, the reporter gene will be expressed. If the cells are dead, the reporter gene will not be expressed. By using this approach, Wu et al (143) injected embryonic cardiomyoblasts expressing either firefly luciferase or HSV1-sr39tk reporter genes that were tracked noninvasively by using optical bioluminescence or micro-PET imaging, respectively (Fig 9). Drastic reductions of signal intensity within the first 1–4 days were noted and were likely due to acute donor cell death from inflammation, adenoviral toxicity, ischemia, and apoptosis. The pattern of cell death was consistent with data in other reports in which invasive assays, such as serial histologic staining (144), terminal transferase uridyl nick end labeling apoptosis assays (145), and TaqMan real-time polymerase chain reaction assays, were used (146).

View larger version (36K): [in this window] [in a new window] [Download PPT slide]   Figure 9: Optical bioluminescence and PET imaging of cell transplantation in rat myocardium. A, Study animal transplanted with embryonic H9c2 cardiomyoblasts emits significant cardiac bioluminescence activity at days 1, 2, 4, 8, 12, and 16 (P < .05 vs control). Control rat shows background signal only. B, The location, magnitude, and duration of cell survival are determined by longitudinal imaging of FHBG activity (gray scale) within the same rat. C, Tomographic views of cardiac micro-PET images shown in short, vertical, and horizontal axes. At day 2, study animal transplanted with cardiomyoblasts expressing HSV1-sr39tk shows significant FHBG uptake (color scale) superimposed on [13N]–NH3 images (gray scale). Control animal shows homogeneous [13N]–NH3 perfusion but background FHBG uptake. D, Autoradiography in the same study animal at day 2 confirms trapping of 18F by transplanted cells at the lateral wall at finer spatial resolution (approximately 50 µm). %ID/g = percentage infective dose per gram, p/sec/cm2/sr = photons per second per square centimeter per steradian. (Reprinted, with permission, from reference 143.)

In the future, it will be important to use these molecular imaging approaches to assess the in vivo biology of different stem cell types. Because of its noninvasive nature, molecular imaging has the potential to help accelerate research progress through evaluation of variables such as the optimal cell type, cell dosage, or delivery route. Perhaps even more important is the investigation of the means aimed at preventing acute donor cell death, which may be the most critical variable for determining the efficacy of stem cell therapy (149–151). Ultimately, the goal is to develop and standardize stem cell transplantation protocols that are safe, quantifiable, and reproducible in the future, thereby avoiding the controversies that have plagued cardiac gene therapy trials (152).

	CONCLUSION

TOP ABSTRACT INTRODUCTION ATHEROSCLEROSIS MYOCARDIAL ISCHEMIA CORONARY ARTERY DISEASE MYOCARDIAL VIABILITY HEART FAILURE CARDIAC GENE THERAPY STEM CELL TRANSPLANTATION CONCLUSION References

 
In summary, molecular imaging is an exciting field. It combines the disciplines of molecular biology, radiochemistry, pharmacology, instrumentation, and clinical medicine into a new imaging paradigm. As discussed in this review, molecular imaging can be used to study cardiac neurotransmission, plaque vulnerability, inflammation, myocardial viability, as well as newer research subjects, such as gene transfer and stem cell survival, that have generated much attention over recent years. Future directions include understanding the molecular mechanisms of individual disease processes, developing newer and more physiologic tracers that target specific disease sites, and implementing multimodality imaging approaches that produce fast throughput analysis in animal studies (optical), high-resolution images (echocardiography, MR imaging), and functional information (SPECT, PET). All of these measures will be essential as the field moves forward from translational animal studies to the clinical arena.

	FOOTNOTES

 

Abbreviations: CAD = coronary artery disease • FDG = fluorine 18 fluorodeoxyglucose • FHBG = 9-(4-[18F]fluoro-3-hydroxymethylbutyl)guanine • HF = heart failure • ICD = implantable cardioverter defibrillator • MI = myocardial infarction • MIBG = m-iodobenzylguanidine • VEGF = vascular endothelial growth factor

Authors stated no financial relationship to disclose.

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