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The recent advent of positron emission tomography (PET) scanners that can image the entire human body opens up intriguing possibilities for cardiovascular research and future clinical applications. These new systems permit radiotracer kinetics to be measured in all organs simultaneously. They are particularly well suited to study cardiovascular disease and its effects on the entire body. They could also play a role in quantitatively measuring physiologic, metabolic, and immunologic responses in healthy individuals to a variety of stressors and lifestyle interventions, and may ultimately be instrumental for evaluating novel therapeutic agents and their molecular effects across different tissues. In this review, we summarize recent progress in PET technology and methodology, discuss several emerging cardiovascular applications for total-body PET, and place this in the context of multiorgan and systems medicine. Finally, we discuss opportunities that will be enabled by the technology, while also pointing to some of the challenges that still need to be addressed. [Display omitted] • Newly developed total-body PET scanners provide opportunities for imaging the entire cardiovascular system simultaneously. • Dynamic imaging of the entire human body at high detection sensitivity and spatial resolution is now possible. • Applications include quantitative total-body imaging of perfusion, blood volume, and metabolism. • Further opportunities are presented by new tracers that target, eg, fibrosis and CD8+ T-cells. [ABSTRACT FROM AUTHOR]

For molecular imaging of atherosclerotic vessel wall activity, tracer kinetic analysis may yield improved contrast versus blood, more robust quantitative parameters, and more reliable characterization of systems biology. The authors introduce a novel dynamic whole-body positron emission tomography (PET) protocol that is enabled by rapid continuous camera table motion, followed by reconstruction of parametric data sets using voxel-based Patlak graphical analysis. Twenty-five subjects were prospectively enrolled and underwent dynamic PET up to 90 minutes after injection of 2-[18F]fluoro-2-deoxy-D-glucose (FDG). Two sets of images were generated: 1) the established standard of static standardized uptake value (SUV) images; and 2) parametric images of the metabolic rate of FDG (MR FDG) using the Patlak plot–derived influx rate. Arterial wall signal was measured and compared using the volume-of-interest technique, and its association with hematopoietic and lymphoid organ signal and atherosclerotic risk factors was explored. Parametric MR FDG images provided excellent arterial wall visualization, with elimination of blood-pool activity, and enhanced focus detectability and reader confidence. Target-to-background ratio (TBR) from MR FDG images was significantly higher compared with SUV images (2.6 ± 0.8 vs 1.4 ± 0.2; P < 0.0001), confirming improved arterial wall contrast. On MR FDG images, arterial wall signal showed improved correlation with hematopoietic and lymphoid organ activity (spleen P = 0.0009; lymph nodes P = 0.0055; and bone marrow P = 0.0202) and increased with the number of atherosclerotic risk factors (r = 0.49; P = 0.0138), where signal from SUV images (SUV max P = 0.9754; TBR max P = 0.8760) did not. Absolute quantification of MR FDG is feasible for arterial wall using dynamic whole-body PET imaging. Parametric images provide superior arterial wall contrast, and they might be better suited to explore the relationship between arterial wall activity, systemic organ networks, and cardiovascular risk. This novel methodology may serve as a platform for future diagnostic and therapeutic clinical studies targeting the biology of arterial wall disease. [Display omitted] [ABSTRACT FROM AUTHOR]

[Display omitted] [ABSTRACT FROM AUTHOR]

As therapeutic approaches have evolved from exogenous bone marrow cell delivery to pharmacological stimulation of endogenous repair, so too has imaging of cardiac repair made significant strides forward. Evaluation of functional outcome remains a staple of noninvasive clinical imaging, which can robustly quantify contractile function, perfusion, and tissue viability. Direct labeling of cells or other novel therapeutics visualizes the whole-body distribution and pharmacokinetics of the therapeutic agent, providing insights into retention, targeting, and drug-tissue interactions. And finally, targeted molecular imaging agents are emerging that may be specifically coupled to drugs targeting the same pathway. This approach enables interrogation of temporal and spatial changes at the molecular level underlying tissue degeneration and regeneration, which facilitates accurate patient selection and timing for therapeutic intervention, as exemplified by recent efforts focusing on the role of inflammation in cardiac repair. The concept of image-guided repair carves out an important and evolving niche for molecular imaging in cardiovascular medicine, with the potential not only to predict outcomes but also to improve patient stratification and progress toward personalized reparative therapy. • Novel cardiovascular therapies increasingly modify molecular targets that may be heterogeneously expressed by patients. • Molecular imaging provides tissue-level information on target expression and drug delivery to guide therapeutic intervention. • Implementing molecular imaging approaches may stratify patient risk and optimize therapeutic delivery to enhance repair. [ABSTRACT FROM AUTHOR]

Cardiovascular magnetic resonance (CMR) has evolved from a pioneering research tool to an established noninvasive imaging method for detecting inducible myocardial perfusion deficits. In this consensus document, experts of different imaging techniques summarize the existing body of evidence regarding CMR perfusion as a viable complement to other established noninvasive tools for the assessment of perfusion and discuss the advantages and pitfalls of the technique. A rapid, standardized CMR perfusion protocol is described, which is safe, clinically feasible, and cost-effective for centers with contemporary magnetic resonance equipment. CMR perfusion can be recommended as a routine diagnostic tool to identify inducible myocardial ischemia. [ABSTRACT FROM AUTHOR]

Objectives An assay for molecular imaging of myocardial CXCR4 expression was evaluated, in order to obtain mechanistic insights noninvasively based on quantitative positron emission tomography (PET). Background The chemokine receptor CXCR4 has emerged as a therapeutic target after acute myocardial infarction (AMI), because of its role in inflammatory and progenitor cell recruitment. Methods PET with the specific CXCR4 ligand, gallium-68 ( 68 Ga)-pentixafor, was performed in mice (n = 53) and compared with ex vivo autoradiography, immunohistochemistry, and left ventricular flow cytometry. In addition, 12 patients were imaged at 2 to 8 days after AMI. Results In mice, 68 Ga-pentixafor identified regional CXCR4 upregulation in the infarct region, peaking at 3 days (infarct/remote [I/R] ratio 1.5 ± 0.2 at 3 days vs. 1.2 ± 0.3 at 7 days; p = 0.03), corresponding to a flow cytometry-based peak of CD45+ leukocytes and immunohistochemical detection of CD68+ macrophages and Ly6G+ granulocytes. Blockade with the CXCR4 antagonist AMD3100 abolished the signal. No specific uptake was found in sham-operated or control animals. Long-term treatment with oral enalapril attenuated the CXCR4 signal (I/R 1.2 ± 0.2 at 3 days and 1.0 ± 0.0.1 at 7 days; p = 0.01 vs. untreated). Patients showed variable degrees of CXCR4 upregulation in the infarct region. No single clinical parameter allowed for prediction of CXCR4 signal strength. At multivariate analysis, a combination of infarct size and time after reperfusion predicted the CXCR4 infarct signal (r multiple = 0.73; p = 0.03). Infarct signal in the myocardium was paralleled by elevated pentixafor uptake in bone marrow (r = 0.61; p = 0.04), which highlighted systemic interactions. Conclusions Targeted PET imaging with 68 Ga-pentixafor identifies the global and regional CXCR4 expression pattern in myocardium and systemic organs. CXCR4 upregulation after AMI coincides with inflammatory cell infiltration, but shows interindividual variability in patients. This may have implications for the response to CXCR4- or other inflammation-targeted therapy, and for subsequent ventricular remodeling. [ABSTRACT FROM AUTHOR]

Molecular imaging enables the visualization and interrogation of specific biologic targets and pathways that precede or underlie changes in morphology, physiology, and function of the heart. Accordingly, it aims at identifying precursors or early stages of cardiac disease, and it may facilitate monitoring and guidance of novel, increasingly specific and versatile cardiovascular therapies. Although SPECT and PET imaging of myocardial metabolism and autonomic innervation are already embedded in clinical practice, various additional targets, probes, and techniques are under development. These techniques hold promise to become a future key in personalizing cardiovascular care. [ABSTRACT FROM AUTHOR]

Positron emission tomography (PET) is a powerful, quantitative imaging modality that has been used for decades to noninvasively investigate cardiovascular biology and physiology. Due to limited availability, methodologic complexity, and high costs, it has long been seen as a research tool and as a reference method for validation of other diagnostic approaches. This perception, fortunately, has changed significantly within recent years. Increasing diversity of therapeutic options for coronary artery disease, and increasing specificity of novel therapies for certain biologic pathways, has resulted in a clinical need for more accurate and specific diagnostic techniques. At the same time, the number of PET centers continues to grow, stimulated by PET''s success in oncology. Methodologic advances as well as improved radiotracer availability have further contributed to more widespread use. Evidence for diagnostic and prognostic usefulness of myocardial perfusion and viability assessment by PET is increasing. Some studies suggest overall cost-effectiveness of the technique despite higher costs of a single study, because unnecessary follow-up procedures can be avoided. The advent of hybrid PET-computed tomography (CT), which enables integration of PET-derived biologic information with multislice CT-derived morphologic information, and the key role of PET in the development and translation of novel molecular-targeted imaging compounds, have further contributed to more widespread acceptance. Today, PET promises to play a leading diagnostic role on the pathway toward a future of high-powered, comprehensive, personalized, cardiovascular medicine. This review summarizes the state-of-the-art in current imaging methodology and clinical application, and outlines novel developments and future directions. [Copyright &y& Elsevier]

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

Background: Given the central importance of the microvasculature in heart transplant recipients, we investigated the possibility of increasing cardiac perfusion after reduction of low-density lipoprotein (LDL)-cholesterol, lipoprotein (a), C-reactive protein (CRP) and fibrinogen plasma levels after apheresis treatment in transplanted patients. Methods: Ten long-term heart transplant recipients were examined with positron emission tomography (PET) to measure myocardial perfusion before and after a single heparin-mediated extracorporeal LDL/fibrinogen precipitation (HELP)-apheresis treatment. PET studies were performed the mornings before and after the apheresis treatment. Myocardial blood flow at rest and during adenosine-induced hyperemia was measured using 13N-ammonia. Results: HELP-apheresis reduced the plasma levels of LDL-cholesterol, lipoprotein (a) and C-reactive protein by 48% (p < 0.001), fibrinogen by 42% (p = 0.02), plasma viscosity by 14% (p = 0.004) and erythrocyte aggregation by 28% (p < 0.02). Osmolality (<1%) and hematocrit (<2%) remained stable. A single apheresis treatment increased median corrected rest flow by 17.5% (p = 0.007) and median hyperemic flow by 27% (p = 0.02). Median coronary flow reserve increased by 8.1% (p = 0.09). Hyperemic flow after adenosine infusion increased plasma vascular endothelial growth factor levels only before HELP-apheresis (+60%), indicating better ischemic tolerance after apheresis (p = 0.01). Conclusions: Myocardial perfusion in transplanted hearts increases significantly after single HELP-apheresis treatment. The present study is only a proof of concept, providing complementary evidence to clinical long-term studies showing that cholesterol reduction either with statins and/or apheresis improves heart transplant outcome. [Copyright &y& Elsevier]

For investigation of the metabolic profile of the transplanted human heart, positron emission tomography with C-11 acetate was performed to compare global and regional oxidative metabolism in 14 transplant patients with that in 10 healthy volunteers. Because no difference between transplants and normals could be observed, the results suggest that oxidative metabolism remains stable after transplantation, whereas cardiac work remains the major determinant. [ABSTRACT FROM AUTHOR]

Molecular Imaging Identifies Fibroblast Activation Beyond the Infarct Region After Acute Myocardial Infarction. [Extracted from the article]

Purpose: To determine the patterns of progression after 68Ga prostate-specific membrane antigen (PSMA)-ligand positron emission tomography (PET)/computed tomography (CT)-guided radiation therapy (RT) for recurrent oligometastatic prostate cancer (PCa).Methods and Materials: One hundred and eight patients with increased prostate-specific antigen levels, who received 68Ga-PSMA-ligand PET/CT-guided RT for recurrent oligometastatic disease after primary therapy for PCa were included. The biochemical progression-free survival and distant disease-free survival after PSMA-ligand PET/CT-guided RT were determined. The patterns of progression were determined using renewed 68Ga-PSMA-ligand PET/CT in patients with biochemical progression and compared with the clinical target volume of the 68Ga-PSMA-ligand PET/CT-guided RT. The frequency of infield and outfield relapses was recorded.Results: A total of 97.2% (105 of 108) of patients showed a decrease in prostate-specific antigen levels after RT and were classified as biochemical responders. After the median follow-up of 18 months, 43.5% (47 of 108) of the patients experienced biochemical progression, resulting in an estimated biochemical progression-free survival of 16 months. Renewed 68Ga-PSMA-ligand PET/CT allowed localization of recurrent disease in 91.7% (33 of 36) of patients. Analysis of the patterns of progression resulted in a cumulative infield relapse rate of 12.1% (4 of 33) and a cumulative outfield relapse rate of 87.9% (29 of 33). The resultant median disease-free survival was 11 months. In terms of the pattern of progression, we observed a shift in the pattern of metastases toward skeletal involvement and distant lymph node metastases. Of these patients, 45.5% (15 of 33) were treated with further RT to delay initiation or escalation of systemic therapies.Conclusion: PSMA-ligand PET/CT-guided RT for relapsed PCa with limited tumor burden allowed individualization of treatment approaches, provided effective local control, and resulted in considerably prolonged biochemical progression-free survival. As indicated by the PSMA-ligand PET/CT-based patterns of progression, repeated PET/CT-guided RT may represent a treatment option in well-selected patients with relapse after RT for oligometastatic disease. [ABSTRACT FROM AUTHOR]

Background: The local inflammatory tissue response after acute myocardial infarction (MI) determines subsequent healing. Systemic interaction may induce neuroinflammation as a precursor to neurodegeneration.Objectives: This study sought to assess the influence of MI on cardiac and brain inflammation using noninvasive positron emission tomography (PET) of the heart-brain axis.Methods: After coronary artery ligation or sham surgery, mice (n = 49) underwent serial whole-body PET imaging of the mitochondrial translocator protein (TSPO) as a marker of activated macrophages and microglia. Patients after acute MI (n = 3) were also compared to healthy controls (n = 9).Results: Infarct mice exhibited elevated myocardial TSPO signal at 1 week versus sham (percent injected dose per gram: 8.0 ± 1.6 vs. 4.8 ± 0.9; p < 0.001), localized to activated CD68+ inflammatory cells in the infarct. Early TSPO signal predicted subsequent left ventricular remodeling at 8 weeks (rpartial = -0.687; p = 0.001). In parallel, brain TSPO signal was elevated at 1 week (1.7 ± 0.2 vs. 1.4 ± 0.2 for sham; p = 0.017), localized to activated microglia. After interval decline at 4 weeks, progressive heart failure precipitated a second wave of neuroinflammation (1.8 ± 0.2; p = 0.005). TSPO was concurrently up-regulated in remote cardiomyocytes at 8 weeks (8.8 ± 1.7, p < 0.001) without inflammatory cell infiltration, suggesting mitochondrial impairment. Angiotensin-converting enzyme inhibitor treatment lowered acute inflammation in the heart (p = 0.003) and brain (p = 0.06) and improved late cardiac function (p = 0.05). Patients also demonstrated elevation of cardiac TSPO signal in the infarct territory, paralleled by neuroinflammation versus controls.Conclusions: The brain is susceptible to acute MI and chronic heart failure. Immune activation may interconnect heart and brain dysfunction, a finding that provides a foundation for strategies to improve heart and brain outcomes. [ABSTRACT FROM AUTHOR]

Background Monocentric and retrospective studies indicate effectiveness of peptide receptor radionuclide therapy targeting somatostatin receptors of neuroendocrine neoplasms. We assessed overall and progression-free survival and adverse events of peptide receptor radionuclide therapy by a multi-institutional, board certified registry with prospective follow-up in five centres in Germany. Methods A total of 450 patients were included and followed for a mean of 24.4 months. Most patients had progressive low- or intermediate grade neuroendocrine neoplasms and 73% were pretreated with at least one therapy. Primary neuroendocrine neoplasms were mainly derived of pancreas (38%), small bowel (30%), unknown primary (19%) or bronchial system (4%). Patients were treated with Lutetium-177 in 54%, with Yttrium-90 in 17% and with both radionuclides in 29%. Overall and progression-free survival was determined with Kaplan–Meier curves and uni-variate log rank test Cox models. Findings Median overall survival of all patients was 59 (95% confidence interval [CI] 49–68.9) months. Overall survival was significantly inferior in the patients treated with Yttrium-90 solely (hazard ratio, 3.22; 95% CI, 1.83–5.64) compared to any peptide receptor radionuclide therapy with Lutetium-177. Grade II (hazard ratio, 2.06; 95% CI, 0.79–5.32) and grade III (hazard ratio, 4.22; 95% CI, 1.41–12.06) neuroendocrine neoplasms had significantly worse overall survival than grade I neuroendocrine neoplasms. Patients with small neuroendocrine neoplasms of small bowel had significantly increased survival (hazard ratio, 0.39; 95% CI, 0.18–0.87) compared to neuroendocrine neoplasms of other locations. Median progression-free survival was 41 (35.9–46.1) months and significantly inferior in patients treated with Yttrium solely (hazard ratio, 2.7; 95% CI, 1.71–4.55). Complete remission was observed in 5.6% of patients, 22.4% had a partial remission, 47.3% were stable and 4% were progressive as best response. Adverse events of bone marrow and kidney function higher than grade III occurred in 0.2–1.5% of patients. Interpretation These results indicate that peptide receptor radionuclide therapy is a highly effective therapy for patients with low to intermediate grade neuroendocrine neoplasms with minor adverse events. [ABSTRACT FROM AUTHOR]

Angiographic severity of coronary artery stenosis has historically been the primary guide to revascularization or medical management of coronary artery disease. However, physiologic severity defined by coronary pressure and/or flow has resurged into clinical prominence as a potential, fundamental change from anatomically to physiologically guided management. This review addresses clinical coronary physiology-pressure and flow-as clinical tools for treating patients. We clarify the basic concepts that hold true for whatever technology measures coronary physiology directly and reliably, here focusing on positron emission tomography and its interplay with intracoronary measurements. [ABSTRACT FROM AUTHOR]

Objectives: The goal of this study was to explore the feasibility of targeted imaging of the angiotensin II type 1 receptor (AT1R) in cardiac tissue, using clinical hybrid positron emission tomography/computed tomography (PET/CT). Background: AT1R is an attractive imaging target due to its key role in various cardiac pathologies, including post-infarct left ventricular remodeling. Methods: Using the novel AT1R ligand [11C]-KR31173, dynamic PET/CT was performed in young farm pigs under healthy conditions (n = 4) and 3 to 4 weeks after experimental myocardial infarction (n = 5). Ex vivo validation was carried out by immunohistochemistry and polymerase chain reaction. First-in-man application was performed in 4 healthy volunteers at baseline and under AT1R blocking. Results: In healthy pigs, myocardial KR31173 retention was detectable, regionally homogeneous, and specific for AT1R, as confirmed by blocking experiments. Metabolism in plasma was low (85 ± 2% of intact tracer after 60 min). After myocardial infarction, KR31173 retention, corrected for regional perfusion, revealed AT1R up-regulation in the infarct area relative to remote myocardium, whereas retention was elevated in both regions when compared with myocardium of healthy controls (8.7 ± 0.8% and 7.1 ± 0.3%/min vs. 5.8 ± 0.4%/min for infarct and remote, respectively, vs. healthy controls; p < 0.01 each). Postmortem analysis confirmed AT1R up-regulation in remote and infarct tissue. First-in-man application was safe, and showed detectable and specific myocardial KR31173 retention, albeit at a lower level than pigs (left ventricular average retention: 1.2 ± 0.1%/min vs. 4.4 ± 1.2%/min for humans vs. pigs; p = 0.04). Conclusions: Noninvasive imaging of cardiac AT1R expression is feasible using clinical PET/CT technology. Results provide a rationale for broader clinical testing of AT1R-targeted molecular imaging. [ABSTRACT FROM AUTHOR]

Dipyridamole is the most common vasodilator used with positron emission tomography for the evaluation of patients with hypertrophic cardiomyopathy (HC). The aim of this study was to evaluate whether positron emission tomographic quantification of regional myocardial perfusion (rMP), myocardial blood flow (MBF), and coronary flow reserve are comparable between dipyridamole and the newer vasodilator regadenoson in HC. An additional aim was to evaluate the association between vasodilator-induced ST-segment depression on electrocardiography and myocardial flow in HC. Nitrogen-13 ammonia positron emission tomography was performed in 57 patients with symptomatic HC at rest and during vasodilator stress (peak) with either dipyridamole (0.56 mg/kg during 4-minute infusion) or regadenoson (0.4 mg fixed bolus dose) for assessment of electrocardiographic findings, rMP (17-segment American Heart Association summed difference score), MBF, and coronary flow reserve. The dipyridamole and regadenoson groups consisted of 28 and 29 patients respectively. Baseline characteristics, including rest MBF (0.92 ± 0.22 vs 0.89 ± 0.23 ml/min/g, p = 0.60), were similar between the 2 groups. During stress, the presence and severity of abnormal rMP (summed difference score 5.5 ± 5.5 vs 5.8 ± 6.7, p = 0.80), peak MBF (1.81 ± 0.44 vs 1.82 ± 0.50 ml/min/g, p = 0.90), and coronary flow reserve (2.02 ± 0.53 vs 2.12 ± 0.12, p = 0.50) were comparable between the dipyridamole and regadenoson groups. Fewer patients exhibited side effects with regadenoson (2 vs 7, p = 0.06). Vasodilator-induced ST-segment depression showed high specificity (about 92%) but low sensitivity (about 34%) to predict abnormal rMP (summed difference score ≥2). In conclusion, measurement of rMP and quantitative flow with positron emission tomography is similar between regadenoson and dipyridamole in patients with symptomatic HC. Regadenoson is tolerated better than dipyridamole and is easier to administer. Vasodilator-induced ST-segment depression is a specific but nonsensitive marker for the prediction of abnormal rMP in patients with HC. [Copyright &y& Elsevier]

Objectives: The aim of this study was to quantify acute myocardial retention of cardiac-derived stem cells (CDCs) and evaluate different delivery methods with positron emission tomography (PET). Background: Success of stem cell transplantation for cardiac regeneration is partially limited by low retention/engraftment of the delivered cells. A clinically applicable method for accurate quantification of cell retention would enable optimization of cell delivery. Methods: The CDCs were derived from syngeneic, male Wistar Kyoto (WK) rats labeled with [18F]-fluoro-deoxy-glucose (18FDG) and injected intramyocardially into the ischemic region of female WK rats after permanent left coronary artery ligation. The effects of fibrin glue (FG), bradycardia (adenosine), and cardiac arrest were examined. Imaging with 18FDG PET was performed for quantification of cell retention. Quantitative polymerase chain reaction (PCR) for the male-specific SRY gene was performed to validate the PET results. Results: Myocardial retention of cells suspended in phosphate-buffered saline 1 h after delivery was 17.6 ± 11.5% by PCR and 17.8 ± 7.3% by PET. When CDCs were injected immediately after induction of cardiac arrest, retention was increased to 75.6 ± 18.6%. Adenosine slowed the ventricular rate and doubled CDC retention (35.4 ± 5.3%). A similar increase in CDC retention was observed after epicardial application of FG at the injection site (37.5 ± 8.2%). The PCR revealed a significant increase in 3-week cell engraftment in the FG animals (22.1 ± 18.6% and 5.3 ± 3.1%, for FG and phosphate-buffered saline, respectively). Conclusions: In vivo PET permits accurate measurement of CDC retention early after intramyocardial delivery. Sealing injection sites with FG or lowering ventricular rate by adenosine might be clinically translatable methods for improving stem cell engraftment in a beating heart. [Copyright &y& Elsevier]

Objectives: We examined the sodium-iodide symporter (NIS), which promotes in vivo cellular uptake of technetium 99m (99mTc) or iodine 124 (124I), as a reporter gene for cell tracking by single-photon emission computed tomography (SPECT) or positron emission tomography (PET) imaging. Background: Stem cells offer the promise of cardiac repair. Stem cell labeling is a prerequisite to tracking cell fate in vivo. Methods: The human NIS complementary deoxyribonucleic acid was transduced into rat cardiac-derived stem cells (rCDCs) using lentiviral vectors. Rats were injected intramyocardially with up to 4 million NIS+-rCDCs immediately after left anterior descending coronary artery ligation. Dual isotope SPECT (or PET) imaging was performed, using 99mTc (or 124I) for cell detection and thallium 201 (or ammonia 13) for myocardial delineation. In a subset of animals, high resolution ex vivo SPECT scans of explanted hearts were obtained to confirm that in vivo signals were derived from the cell injection site. Results: NIS expression in rCDCs did not affect cell viability and proliferation. NIS activity was verified in isolated transduced cells by measuring 99mTc uptake. NIS+ rCDCs were visualized in vivo as regions of 99mTc or 124I uptake within a perfusion deficit in the SPECT and PET images, respectively. Cells could be visualized by SPECT up to 6 days post-injection. Ex vivo SPECT confirmed that in vivo 99mTc signals were localized to the cell injection sites. Conclusions: Ectopic NIS expression allows noninvasive in vivo stem cell tracking in the myocardium, using either SPECT or PET. The general approach shows significant promise in tracking the fate of transplanted cells participating in cardiac regeneration, given its ability to observe living cells using clinically applicable imaging modalities. [Copyright &y& Elsevier]

Objectives: The aim of this study was to characterize the relationship between impaired sympathetic innervation and arrhythmia with noninvasive biologic imaging in an animal model of post-infarct ventricular tachycardia (VT). Background: Innervation might be abnormal in the normally perfused borderzone of myocardial infarction, contributing to myocardial catecholamine overexposure and arrhythmogenic risk. Methods: Myocardial infarction was induced by mid-left anterior descending coronary artery balloon occlusion in 11 pigs. Positron emission tomography (PET) of tissue perfusion and catecholamine uptake and storage was performed with [13N]-ammonia and [11C]-epinephrine 4 to 12 weeks later. Magnetic resonance imaging and invasive electrophysiology (electroanatomic mapping, basket catheter, VT inducibility) were performed within 1 week of PET. Results: When compared with a normal database of 9 healthy animals, reduced perfusion was observed in 37 ± 7% of the left ventricle (LV). Epinephrine retention was reduced in 44 ± 7% of LV, resulting in a perfusion/innervation mismatch of 7 ± 4% LV. Sustained monomorphic VT was inducible in 7 of 11 animals. These animals showed a larger perfusion/innervation mismatch (10 ± 4% vs. 4 ± 2% LV for animals without VT; p = 0.02). Regionally, the degree of perfusion/innervation mismatch did not correlate with wall thickness or thickening but showed a significant correlation with reduced myocardial voltage (r = 0.93; p = 0.001) and with the site of earliest VT activation (chi-square 13.1; p < 0.001). Conclusions: Noninvasive mapping of cardiac sympathetic nerve terminals reveals regionally impaired catecholamine uptake and storage in the normally perfused borderzone after experimental myocardial infarction. These areas might be useful to characterize the individual risk for ventricular arrhythmia. [Copyright &y& Elsevier]

Objectives: We sought to investigate the usefulness of integrated positron emission tomography (PET) and computed tomography (CT) for in vivo characterization of an angiogenesis-directed molecular intervention. Background: Controversies about the effectiveness of molecular therapies for cardiovascular disease have prompted the need for more powerful noninvasive imaging techniques. Methods: In a model of regional adenoviral transfer of the VEGF121 gene to myocardium of healthy pigs, PET-CT using multiple molecular-directed radiotracers was employed. Results: Two days after gene transfer, successful transgene expression was noninvasively confirmed by a reporter probe targeting co-expressed HSV1-sr39tk reporter gene. The CT-derived ventricular function and morphology remained unaltered (left ventricular ejection fraction 57 ± 5% in adenovirus-injected animals vs. 53 ± 5% in controls; p = 0.36). Increased regional perfusion was identified in areas overexpressing VEGF (myocardial blood flow during adenosine-induced vasodilation 1.47 ± 0.49 vs. 1.14 ± 0.27 ml/g/min in remote areas; p = 0.01), corroborating in vivo effects on microvascular tone and permeability. Finally, regional angiogenesis-associated αvβ3 integrin expression was not enhanced, suggesting little contribution to the perfusion increase. Fusion of CT morphology and tracer-derived molecular signals allowed for accurate regional localization of biologic signals. Findings were validated by control vectors, sham-operated animals, and ex vivo tissue analysis. Conclusions: Integrated PET-CT has the potential to dissect cardiovascular biologic mechanisms from gene expression to physiologic function and morphology. The VEGF overexpression in healthy myocardium increases myocardial perfusion without significant up-regulation of αvβ3 integrin adhesion molecules early after the intervention. [Copyright &y& Elsevier]