Frank M. Bengel

Guidelines on the diagnosis and management of acute pulmonary embolism: the Task Force for the Diagnosis and Management of Acute Pulmonary Embolism of the European Society of Cardiology (ESC).

Non-thrombotic PE does not represent a distinct clinical syndrome. It may be due to a variety of embolic materials and result in a wide spectrum of clinical presentations, making the diagnosis difficult. With the exception of severe air and fat embolism, the haemodynamic consequences of non-thrombotic emboli are usually mild. Treatment is mostly supportive but may differ according to the type of embolic material and clinical severity.

EANM/ESC procedural guidelines for myocardial perfusion imaging in nuclear cardiology

The European procedural guidelines for radionuclide imaging of myocardial perfusion and viability are presented in 13 sections covering patient information, radiopharmaceuticals, injected activities and dosimetry, stress tests, imaging protocols and acquisition, quality control and reconstruction methods, gated studies and attenuation-scatter compensation, data analysis, reports and image display, and positron emission tomography. If the specific recommendations given could not be based on evidence from original, scientific studies, we tried to express this state-of-art. The guidelines are designed to assist in the practice of performing, interpreting and reporting myocardial perfusion SPET. The guidelines do not discuss clinical indications, benefits or drawbacks of radionuclide myocardial imaging compared to non-nuclear techniques, nor do they cover cost benefit or cost effectiveness.

Anatomic versus physiologic assessment of coronary artery disease. Role of coronary flow reserve, fractional flow reserve, and positron emission tomography imaging in revascularization decision-making.

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.

Noninvasive quantification and optimization of acute cell retention by in vivo positron emission tomography after intramyocardial cardiac-derived stem cell delivery.

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 [(18)F]-fluoro-deoxy-glucose ((18)FDG) 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 (18)FDG 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.

Cardiac positron emission tomography.

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 PETs 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.

Multimodality Cardiovascular Molecular Imaging, Part II

Molecular imaging has the potential to profoundly impact preclinical research and future clinical cardiovascular care. In Part I of this 2-part consensus article on multimodality cardiovascular molecular imaging, the imaging methodology, evolving imaging technology, and development of novel targeted molecular probes relevant to the developing field of cardiovascular molecular imaging were reviewed.1 Part II of this consensus article will review the targeted imaging probes available for the identification and evaluation of critical pathophysiological processes in the cardiovascular system. These include novel imaging strategies for the evaluation of inflammation, thrombosis, apoptosis, necrosis, vascular remodeling, and angiogenesis. The current article will also review the role of targeted imaging of a number of cardiovascular diseases, including atherosclerosis, ischemic injury, postinfarction remodeling, and heart failure, as well as the emerging fields of regenerative, genetic, and cell-based therapies. Special emphasis is placed on multimodal imaging, as these hybrid techniques promise to advance the field by combining approaches with complementary strengths and off-setting limitations.2,3 Although some applications of molecular imaging are well established, other clinical applications are under development and still emerging, such as early detection of atherosclerosis or unstable plaque.4 The goals of molecular imaging are to refine risk assessment, facilitate the early diagnosis of disease before the occurrence of debilitating events, aid in the development of personalized therapeutic regimens and to monitor the efficacy of complex therapies. However, to translate the evolving targeted imaging probes, technologies, and applications into clinical care, the imaging community will need to overcome several hurdles. Therefore, the current review will also discuss the opportunities and challenges associated with the implementation and advancement of targeted molecular imaging in clinical practice, and the realization of image-directed personalized medicine.

Extent of Cardiac Sympathetic Neuronal Damage Is Determined by the Area of Ischemia in Patients With Acute Coronary Syndromes

BACKGROUND Prior studies have demonstrated that acute ischemic injury causes sympathetic neuronal damage exceeding the area of necrosis. The aim of this study was to test the hypothesis that sympathetic neuronal damage measured by (123)I-metaiodobenzylguanidine (MIBG) imaging would be determined by the area of ischemia as reflected by area at risk in patients undergoing reperfusion therapy for acute coronary syndromes. METHODS AND RESULTS In 12 patients, the myocardium at risk was assessed by (99m)Tc-sestamibi SPECT before reperfusion, and infarct size was measured by follow-up (99m)Tc-sestamibi SPECT 1 week later. All patients also underwent (123)I-MIBG SPECT within a mean of 11 days after onset. The SPECT image analysis was based on a semiquantitative polar map approach. Defect size on the (123)I-MIBG or (99m)Tc-sestamibi SPECT was measured for the left ventricle (LV) with the use of a threshold of -2.5 SD from the mean value of a normal database and was expressed as %LV. The (123)I-MIBG defect size (47+/-18%LV) was larger than the infarct size (27+/-23%LV, P<0. 001) but was similar to the risk area (49+/-18%LV, P=NS). Furthermore, the (123)I-MIBG defect size was closely correlated with the risk area (r=0.905, P<0.001). CONCLUSIONS Sympathetic neuronal damage measured by (123)I-MIBG SPECT is larger than infarct size and is closely related to risk area, suggesting high sensitivity of neuronal structures to ischemia compared with myocardial cells.

Ectopic Expression of the Sodium-Iodide Symporter Enables Imaging of Transplanted Cardiac Stem Cells In Vivo by Single-Photon Emission Computed Tomography or Positron Emission Tomography

OBJECTIVES We examined the sodium-iodide symporter (NIS), which promotes in vivo cellular uptake of technetium 99m ((99m)Tc) or iodine 124 ((124)I), 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 (99m)Tc (or (124)I) 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 (99m)Tc uptake. NIS(+) rCDCs were visualized in vivo as regions of (99m)Tc or (124)I 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 (99m)Tc 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.

Prediction of Short-Term Cardiovascular Events Using Quantification of Global Myocardial Flow Reserve in Patients Referred for Clinical 82Rb PET Perfusion Imaging

Current noninvasive tests for coronary artery disease detect atherosclerosis or regional ischemia. Global myocardial flow reserve is not routinely identified, although it may be an additional marker of disease development and progression. Methods: For the clinical work-up of suspected or known stable coronary artery disease, 275 individuals had undergone rest–dipyridamole 82Rb myocardial perfusion imaging using PET. In addition to clinical measures of regional perfusion and function, an experimentally validated approach to quantify global myocardial flow reserve was used. Follow-up was obtained for 362 ± 277 d. Results: Myocardial blood flow and flow reserve showed significant correlation to systemic and cardiac hemodynamics and a weak association with risk factors such as age and history of hyperlipidemia. Flow reserve was expectedly lower in subjects with regional ischemia (1.70 ± 0.65 vs. 2.31 ± 0.97 in those without; P < 0.0001), but a wide range was observed in those without regional perfusion abnormalities. We used a composite endpoint of hard and soft events to determine that flow reserve below the median was predictive of adverse outcome in the overall population (P = 0.001) and in subjects with normal regional perfusion (n = 178; P = 0.036), whereas stress flow was predictive only in the overall population (P = 0.001). Age-adjusted multivariate analysis confirmed regional perfusion defects (relative hazard, 2.51; 95% confidence interval, 1.24–5.10; P = 0.009) and low global flow reserve (relative hazard, 2.93; 95% confidence interval, 1.30–6.65; P = 0.011) as independent predictors of cardiac events. Conclusion: In clinical cardiac 82Rb PET, globally impaired flow reserve is a relevant marker for predicting short-term cardiovascular events. It may be used for integration with currently established functional and morphologic test results and for guidance of preventive measures, especially in the absence of regional flow–limiting disease.

Serial Assessment of Sympathetic Reinnervation After Orthotopic Heart Transplantation A Longitudinal Study Using PET and C-11 Hydroxyephedrine

BACKGROUND Little is known about the progressiveness of sympathetic reinnervation late after cardiac transplantation (HTX). The aim of the present study was to describe individual growth of sympathetic terminals after HTX by a longitudinal quantitative assessment. METHODS AND RESULTS In 20 patients after HTX, dynamic PET with C-11 hydroxyephedrine (HED) was performed twice within 3.0+/-0.5 years. According to the time interval between HTX and first PET, subgroups of patients early (group A, <1.5 years; n=7), intermediate (group B, 1.5 to 7 years; n=7) and late (group C, >7 years; n=6) after HTX were defined. At the time of first HED PET, 10 patients were completely denervated (7 in group A, 2 in group B, and 1 in group C). Only 3 remained denervated at second PET. A significant increase of reinnervated myocardium between first and second PET was found in all 3 groups (0% to 9+/-9% of left ventricle for group A, P<0.05; 13+/-12% to 23+/-17% for group B, P<0.05; 21+/-21% to 37+/-23% for group C, P<0.05). The magnitude of increase was similar between groups. Reinnervation was first surveyed in the basal anterior region, then toward apex, septal, and lateral wall. Inferior wall remained denervated. The largest reinnervated area surveyed in an individuum was 66% of the left ventricle. CONCLUSIONS The present data confirm the low likelihood of sympathetic reinnervation within 18 months after HTX. Once the reinnervation process is initiated, a continuous growth is observed even late after HTX, suggesting a progressive nature of reinnervation. Reinnervation, however, remained regionally heterogeneous, and a complete restoration was not found until 15 years after HTX.