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What can we learn about valvular heart disease from PET/CT?
Future Cardiology
Abstract
Valvular heart disease is a major cause of morbidity and mortality, and with an aging population, its prevalence is increasing. Here, we review the evolving use of positron emission tomography/computed tomography in valvular heart disease, with particular focus on calcific aortic stenosis and infective endocarditis. In principle, the activity of any pathological process can be studied, as long as an appropriate radiotracer can be developed. We will review some of the early data using established tracers in the above and other conditions, providing discussion as to the future research and clinical roles of these techniques. Furthermore, we will discuss the potential impact of novel tracers that are currently under development or testing in preclinical models. It is hoped that such advanced imaging might improve the diagnosis, treatment and outlook for patients with valvular heart disease.
... The current method of diagnosis uses modified Duke criteria (MDC), which are divided into "major criteria" (typical blood culture and positive echocardiography) and "minor criteria" (predisposition, fever, vascular phenomena, immunologic phenomena, suggestive echocardiogram, and suggestive microbiologic findings). However, it creates a problem for patients with equivocal clinical symptoms in the absence of conventional echocardiographic features (particularly when prosthetic heart valves are present), making the diagnosis difficult [23]. Imaging modalities such as transesophageal echocardiogram (TEE), CT, and magnetic resonance imaging (MRI) have been studied. ...
The application of [18F]-fluorodeoxyglucose ([18F]FDG) as a radiotracer to detect sites of inflammation (either due to bacterial infection or primary inflammation) has led to exploring the role of PET in visualizing bacteria directly at sites of infection. However, the results from such efforts are controversial and inconclusive so far. We aimed to assess the limitations of PET as an effective modality in the diagnosis of bacterial infections. Inflammation due to bacterial infections can be visualized by using [18F]FDG-PET. However, the non-specificity of [18F]FDG makes it undesirable to visualize bacteria as the underlying cause of inflammation. Hence, more specific radiotracers that possibly bind to or accumulate in bacteria-specific receptors or enzymes are being explored. Several radiotracers, including 2-deoxy-2-[18F]fluorosorbitol ([18F]FDS), 6-[18F]-fluoromaltose, [11C]para-aminobenzoic acid ([11C]PABA), radiolabeled trimethoprim (11C-TMP) and its analog fluoropropyl-trimethoprim (18F-FPTMP), other radiolabeled sugars, and antimicrobial drugs have been used to image microorganisms. Unfortunately, no progress has been made in translating the results to routine human use; feasibility and other factors have constrained their success in clinical settings. In the current article, we discuss the limitations of direct bacterial visualization with PET tracers, but emphasize the important role of [18F]FDG-PET as the only option for detecting evidence of infection.
... Accordingly, 18 F-NaF uptake by PET is being used to track progression of AS in an ongoing clinical trial of bisphosphonates and RANK-ligand inhibitors (NCT02132026). It follows from these data that 18 F-NaF could also potentially be applied in the evaluation of mitral annular calcification, an under-studied and increasingly frequent cause of mitral valve disease (59). ...
The application of positron emission tomography (PET) to cardiac disease has yielded tremendous developments in the evaluation of coronary artery, myocardial, and valvular heart disease over the past several decades. These advances have included development of new radiotracers, incremental technological improvements, and coupling of PET with other non-invasive cardiac imaging modalities. The current era has seen rapid, successive and wide-ranging advances in PET myocardial perfusion and metabolic imaging. This review will address emerging techniques in cardiovascular PET imaging, including the measurement of absolute myocardial blood flow (MBF), use of novel tracers, and other advances in heart failure, infection imaging, and valvular disease.
... Recently, the novel application of hybrid PET/CT imaging has been used to study patients with aor- tic stenosis, providing unique and important insights into its pathophysiology. 29 ...
... Modern CT is the result of both clinical need and technological problems [19]. The use of CT in nuclear medicine has been growing, first with the introduction of positron emission tomography (PET) combined with CT (PET/CT) [20] and, more recently, with the introduction single-photon emission CT (SPECT) combined with CT (SPECT/CT) [21]. In addition, some of the basic CT tools, such as reconstruction from projections (i.e., data measured at many positions and angles), are very similar to those underlying the nuclear medicine cross-sectional imaging modalities PET and SPECT. ...
Coronary artery calcification (CAC) imaging is widely used for the assessment of patients at moderate risk of cardiovascular disease. It is more logical and practical to detect preclinical coronary artery disease (CAD) rather than to make predictions based solely on risk factor assessment. Furthermore, CAC imaging leads to the reclassification of a significant proportion of moderate-risk patients into lower or higher risk categories. In higher-risk patients, including for example those with diabetes, a higher prevalence of CAC has been shown to be associated with a high short-term risk of cardiovascular events, while those with a zero calcium score have excellent event-free survival, similar to survival in nondiabetic patients. Having a zero calcium score is currently used in UK practice guidelines as a criterion for further investigations in patients presenting to emergency departments with chest pain. Unanswered questions include the concept of CAC progression that needs to be standardized with respect to technique, interpretation and subsequent management strategies. Recent studies have also demonstrated that risk assessment using CT is motivational to patients leading to better adherence to their preventive practices as well as medication. However, statin has not proved to be consistently beneficial in slowing the CAC progression rate, but does significantly reduce cardiovascular events in patients with increased CAC. Screening asymptomatic subjects to target measures for the prevention of cardiovascular events remains a major challenge. The established primary prevention risk-scoring methods use equations derived from large prospective cohort studies, but further fine-tuning of cardiovascular risk assessment remains important as 25 % of individuals with a low estimated risk may experience cardiac events. In this modern scientific world, the addition of CT is the best tool to add to the diagnostic work-up of CAD, as validated by multiple population-based studies and large-scale clinical trials.
... It has emerged as a potentially useful prognostic marker in patients with heart failure, having recently been associated with all-cause mortality in a community-based study[111][112][113][114]. We believe this simple blood test will hold similar promise in aortic stenosis. 18 F-Fluciclatide is a PET tracer that has a high affinity for extracellular integrin receptors, thereby acting as a marker of fibrosis activity[115]. Indeed, these integrin receptors are upregulated in states of fibrosis[116,117]and our preliminary data in patients with myocardial infarction indicate that 18 F-Fluciclatide activity does indeed map to regions of infarction. ...
Calcified aortic stenosis is a condition that affects the valve and the myocardium. As the valve narrows, left ventricular hypertrophy occurs initially as an adaptive mechanism to maintain cardiac output. Ultimately, the ventricle decompensates and patients transition towards heart failure and adverse events. Current guidelines recommend aortic valve replacement in patients with severe aortic stenosis and evidence of decompensation based on either symptoms or an impaired ejection fraction <50%. However, symptoms can be subjective and correlate only modestly with the severity of aortic stenosis whilst impaired ejection fraction is an advanced manifestation and often irreversible. In this review, the authors will discuss the pathophysiology of left ventricular hypertrophy and the transition to heart failure. Subsequently, the authors will examine novel biomarkers that may better identify the transition from hypertrophy to heart failure and therefore guide the optimal timing for aortic valve replacement.
Valvular heart disease (VHD) is when any of the heart valves are diseased or damaged and account for up to a quarter of all cardiac surgical procedures in the United States. Understanding the natural history and complexities of VHD has evolved primarily because of the increased use of multimodality imaging. Many of the imaging types discussed are incorporated into routine clinical practice. These advances, in conjunction with expanded interventional cardiology and surgical technology and approaches have resulted in timely diagnosis, accurate grading of severity, and informed patient selection for therapeutic interventions. More recently, imaging has played an integral role in procedural planning, real-time procedural guidance and complication mitigation, and assessment of outcomes. This review provides an overview of the current evidence for the use of imaging in VHD, and how various approaches can be used in clinical practice.
Aortic valve stenosis is the commonest form of valvular heart disease in the Western world, currently affecting about 7% of the population over the age of 60, while 3% of people over the age of 75 have severe stenosis. With an aging population, its prevalence is expected to increase dramatically in the next few decades with major financial implications for global healthcare systems. Aortic stenosis is characterized by progressive valve narrowing that leads to a high-pressure load on the left ventricle (LV), triggering hypertrophy of cardiac myocytes, and increase in LV wall thickness and mass.
Purpose of Review
Infective endocarditis (IE) remains a deadly disease despite improvements in its management. Echocardiography is crucial for the diagnosis of IE; however, its value is operator-dependent and its sensitivity can decrease in the presence of valvular prosthesis. This review aims to provide an overview on the role of nuclear cardiac imaging in the diagnosis of IE.
Recent Findings
Among all nuclear cardiac imaging modalities, both radiolabeled leukocyte scintigraphy and 2-deoxy-2-[fluorine-18]fluoro-D-glucose positron emission tomography/computed tomography ([¹⁸F]FDG-PET/CT) have been recently introduced in the guidelines of European Society of Cardiology (ESC) for the management of IE. The ESC guidelines included some minor criteria (mainly clinical), and two different sets of major criteria based on blood culture and imaging, respectively. The positivity of either radiolabeled leukocyte scintigraphy or [¹⁸F]FDG-PET/CT images is considered itself a major criterion to diagnose IE. However, nuclear cardiac imaging analysis may be tricky and methodological and technical aspects should be carefully considered.
Summary
Available evidence supports the role of nuclear cardiac imaging in the diagnosis and management of IE. However, all practitioners who act within the “Endocarditis Team” should present a very high level of expertise.
Functional tricuspid regurgitation (TR) is mainly due to disruption in the geometry of the tricuspid annulus secondary to tricuspid annular dilatation and right ventricular enlargement with or without pulmonary hypertension. Multiple imaging modalities have been used to evaluate the severity of functional TR. Echocardiography remains the most widely utilized modality for TR assessment but there is a growing role for cardiac magnetic resonance imaging which has better spatial and temporal resolution. Multi-modality imaging techniques are sometimes needed for adequately assessing the severity of functional TR.
As laparoscopic surgery is replacing open surgery, similarly computed tomography angiography is replacing invasive conventional cardiac angiography. In the last century, marvelous efforts in research have improved strategies for cure, diagnosis and prevention of fatal human diseases; however, coronary artery disease, as the most prevalent cause of mortality and morbidity in the world, has remained a great challenge. Due to advancements in technology and research, it has become more simple and robust to diagnose and treat coronary artery disease (CAD) with minimal or no intervention, promising to not only diagnosis at an early stage but potential prevention altogether. While most with obvious CAD can be diagnosed easily and quickly with ECG, those identified as 'low risk' require more extensive testing to diagnose or rule out CAD. For example in emergency departments, low-risk patients with chest pain are diagnosed solely depending on history, ECG and blood testing for biomarkers. This approach has resulted in either delayed or miss-diagnosis of Acute coronary syndrome. To prevent this, many emergency departments now use protocols for low-risk heart patients that include cardiac stress tests and/or CT heart imaging. This review provides an overview of the current literature on the value of Computed tomography angiography and discusses how prognostic information obtained with Computed tomography angiography can be used to further integrate the technique into clinical practice.
AimsThe pathophysiology of aortic stenosis shares many similarities with atherosclerosis and skeletal bone formation. Using non-invasive imaging, we compared aortic valve calcification and inflammation activity with that measured in atherosclerosis and bone.Methods and resultsPositron emission and computed tomography was performed using 18F-sodium fluoride (18F-NaF, calcification) and 18F-fluorodeoxyglucose (18F-FDG, inflammation) in 101 patients with calcific aortic valve disease (81 aortic stenosis and 20 aortic sclerosis). Calcium scores and positron emission tomography tracer activity (tissue-to-background ratio; TBR) were measured in the aortic valve, coronary arteries, thoracic aorta, and bone. Over 90% of the cohort had coexistent calcific atheroma, yet correlations between calcium scores were weak or absent (valve vs. aorta r(2) = 0.015, P = 0.222; valve vs. coronaries r(2) = 0.039, P = 0.049) as were associations between calcium scores and bone mineral density (BMD vs. valve r(2) = 0.000, P = 0.766; vs. aorta r(2) = 0.052, P = 0.025; vs. coronaries r(2) = 0.016, P = 0.210). 18F-NaF activity in the valve was 28% higher than in the aorta (TBR: 2.66 ± 0.84 vs. 2.11 ± 0.31, respectively, P < 0.001) and correlated more strongly with the severity of aortic stenosis (r(2) = 0.419, P < 0.001) than 18F-NaF activity outwith the valve (valve vs. aorta r(2) = 0.167, P < 0.001; valve vs. coronary arteries r(2) = 0.174, P < 0.001; valve vs. bone r(2) = 0.001, P = 0.806). In contrast, 18F-FDG activity was lower in the aortic valve than the aortic atheroma (TBR: 1.56 ± 0.21 vs. 1.81 ± 0.24, respectively, P < 0.001) and more closely associated with uptake outwith the valve (valve vs. aorta r(2) = 0.327, P < 0.001).Conclusion
In patients with aortic stenosis, disease activity appears to be determined by local calcific processes within the valve that are distinct from atherosclerosis and skeletal bone metabolism.Trial Registration: ClinicalTrials.gov number: NCT01358513.
Inflammatory disorders of the cardiovascular system can affect the myocardium, pericardium, or vessel walls. Patients with myocardial and pericardial disease may present with chest pain, palpitations, and shortness of breath, symptoms resembling myocardial ischemia or infarction. The manifestations of vasculitis may include fever, weight loss, and fatigue, mimicking infectious or malignant processes. Because of the difficulty of differentiating these disease processes, patients frequently undergo multiple diagnostic examinations before obtaining a final diagnosis of myocarditis, pericarditis, or vasculitis. Computed tomography (CT) and magnetic resonance imaging play important roles in the assessment of structural abnormalities of the cardiovascular system, and combined positron emission tomography (PET) and CT may depict inflammatory processes before structural changes occur. Familiarity with the PET/CT appearances of inflammatory processes in the myocardium, pericardium, and vessels is important for accurate and prompt diagnosis.
Coagulase-positive Staphylococcus aureus (S. aureus) is the major causal pathogen of acute endocarditis, a rapidly progressing, destructive infection of the heart valves. Bacterial colonization occurs at sites of endothelial damage, where, together with fibrin and platelets, the bacteria initiate the formation of abnormal growths known as vegetations. Here we report that an engineered analog of prothrombin could be used to detect S. aureus in endocarditic vegetations via noninvasive fluorescence or positron emission tomography (PET) imaging. These prothrombin derivatives bound staphylocoagulase and intercalated into growing bacterial vegetations. We also present evidence for bacterial quorum sensing in the regulation of staphylocoagulase expression by S. aureus. Staphylocoagulase expression was limited to the growing edge of mature vegetations, where it was exposed to the host and co-localized with the imaging probe. When endocarditis was induced with an S. aureus strain with genetic deletion of coagulases, survival of mice improved, highlighting the role of staphylocoagulase as a virulence factor.
The objective of this study is to systematically review the role of positron emission tomography (PET) and PET/computed tomography (PET/CT) with fluorine-18-fluorodeoxyglucose (FDG) in patients with large-vessel vasculitis (LVV). A comprehensive literature search of published studies through April 2011 in PubMed/MEDLINE and Scopus databases regarding whole-body FDG-PET and PET/CT in patients with LVV was performed. We identified 32 studies including 604 LVV patients. The main findings of these studies are presented. The conclusions are the following: (1) FDG-PET and PET/CT are useful imaging methods in the initial diagnosis and in the assessment of activity and extent of disease in patients with LVV; (2) the correlation between FDG-PET findings and serological levels of inflammatory markers, as well as the usefulness of FDG-PET and PET/CT in evaluating treatment response, remains unclear; (3) it appears that there is a superiority of FDG-PET and PET/CT over conventional imaging methods in the diagnosis of LVV, but not in assessing disease activity under immunosuppressive treatment, in predicting relapse or in evaluating vascular complications; and (4) given the heterogeneity between studies with regard to PET analysis and diagnostic criteria, a standardization of the technique is needed.
Apoptosis, or programmed cell death (PCD), contributes to the decline in ventricular function in heart failure. Because apoptosis comprises a programmed cascade of events, it is potentially reversible, and timely intervention should delay the development of cardiomyopathy. (99m)Tc-Labeled annexin A5 has successfully been used for the noninvasive detection of PCD in myocardial infarction and heart transplant rejection. The present study evaluated the role of annexin A5 imaging for detection of PCD in heart failure patients.
Annexin A5 imaging was performed on 9 consecutive heart failure patients with advanced nonischemic cardiomyopathy (dilated, n = 8; hypertrophic, n = 1) and in 2 relatives having the same genetic background as the hypertrophic cardiomyopathy patient but no heart failure.
Four of the patients with dilated cardiomyopathy and the 1 with hypertrophic cardiomyopathy and heart failure showed focal, multifocal, or global left ventricular uptake of annexin A5. No uptake was visualized in the remaining 4 patients or in the 2 controls. All cases showing annexin A5 uptake within the left ventricle experienced significant reduction in left ventricular function or functional class. In cases with no annexin A5 uptake, left ventricular function and clinical status remained stable.
These data indicate the feasibility of noninvasive PCD detection with annexin imaging in heart failure patients. Annexin A5 uptake is associated with deterioration in left ventricular function, and this association may lend itself to the development of novel management strategies.
A 62-year-old man presented to a district general hospital with a 4-week history of fever, drenching sweats, lethargy and intermittent thoracic back pain. Two weeks prior to onset, a pacemaker had been inserted for recurrent syncope secondary to carotid sinus hypersensitivity. His other past medical history included a permanent tracheostomy following resection of a laryngeal carcinoma 8 years previously, and ischaemic heart disease. The latter culminated in an acute coronary syndrome 7 months before the current presentation, for which primary angioplasty was undertaken with insertion of six drug-eluting coronary artery stents requiring dual antiplatelet therapy for at least 1 year.
On admission , he was febrile at 38.5°C. There were no peripheral stigmata of infective endocarditis, auscultation of the pre-cordium identified no murmurs and the pacemaker site was not inflamed. Systemic examination was otherwise unremarkable, as were chest radiography and urinalysis. Transthoracic echocardiography demonstrated good systolic function, with no valvular regurgitation or pacemaker lead vegetations. In the absence of a clear septic focus, he was commenced on piperacillin–tazobactam. Blood tests showed haemoglobin of 11.6 g/dl, white cell count of 5.7 × 109 cells/l and platelet count of 52 × 109 cells/l. C-reactive protein (CRP) was elevated at 272 mg/l. Coagulation screen was normal. Multiple blood cultures were drawn, which grew methicillin-sensitive Staphylococcus aureus . Intravenous flucloxacillin and rifampicin were commenced.
He was consequently transferred to the London Heart Hospital for further management. The pacemaker was explanted and there was marked clinical improvement. Nonetheless, despite antibiotic therapy he continued to have high-grade pyrexias, without diurnal variation, and elevated serum CRP concentrations. An extensive septic screen, including urine and blood cultures, chest radiographs and repeated transthoracic and transoesophageal echocardiograms revealed no abnormalities.
Computed tomography (CT) scan of the thorax, abdomen and pelvis to identify any occult septic focus revealed a large infrarenal aortic aneurysm, as well …
The haemorrhage in the plaque (intraplaque haemorrhage) plays a critical role in the progression of atherosclerosis. The purpose of this study is to clarify whether the haemorrhage in the aortic valve leaflet (intraleaflet haemorrhage) accelerates the progression of aortic valve stenosis (AS).
We examined specimens of aortic valve leaflets obtained from 36 patients who had undergone aortic valve replacement for degenerative AS and in whom echocardiographic data were available just before the operation and at least 180 days before the last study. The stenotic valves were examined by immunohistochemistry to detect intraleaflet haemorrhage with antibody against glycophorin A, an erythrocyte-specific protein. The progression of AS was assessed by annualized change in the aortic valve area (ΔAVA: cm(2)/year). The patients were divided into two groups, namely the rapid progression group (ΔAVA ≥ 0.1 cm(2)/year) and the slow progression group (ΔAVA < 0.1 cm(2)/year), according to the reported average progression rate of AS. Intraleaflet haemorrhage was observed in 78 % of the specimens. Intraleaflet haemorrhage was associated with neovascularization and macrophage infiltration. The areas of intraleaflet haemorrhage and macrophage infiltration were greater in the rapid progression group than in the slow progression group. Multivariate analysis has shown that the area of intraleaflet haemorrhage was the sole independent factor that positively correlated with ΔAVA.
Intraleaflet haemorrhage was frequently observed in the valve leaflets of degenerative AS and associated with a rapid progression of AS.
The clinical feasibility of noninvasive imaging of interstitial alterations after myocardial infarction (MI) was assessed using a technetium-99m-labeled RGD imaging peptide (RIP). In experimental studies, RIP has been shown to target integrins associated with collagen-producing myofibroblasts (MFB).
Ten patients underwent myocardial perfusion imaging (MPI) within the first week after MI. At 3 and 8 weeks after MI, RIP was administered intravenously and SPECT images acquired for interstitial imaging. RIP imaging was compared to initial MPI and to the extent of scar formation defined by late gadolinium-enhanced (LGE) cardiac magnetic resonance (CMR) imaging 1 year after MI. RIP uptake was observed in 7 of the 10 patients at both 3 and 8 weeks. Although, RIP uptake corresponded to areas of perfusion defects, it usually extended beyond the infarct zone to a variable extent; 2 of 7 patients showed tracer uptake throughout myocardium. In all positive cases, RIP uptake was similar to the extent of scar observed at 1 year by LGE-CMR imaging.
This study demonstrates that RGD-based imaging early after MI may predict the eventual extent of scar formation, which often exceeds initial MPI deficit but colocalizes with LGE in CMR imaging performed subsequently.
Measurements of [(18)F]fluorodeoxyglucose (FDG) uptake as a potential marker of the inflammatory activity of the vessel wall could be useful to identify vulnerable atherosclerotic plaques. The purpose of this study was to correlate the FDG uptake in the left anterior descending coronary artery (LAD) with cardiovascular risk factors, pericardial fat volume (PFV) and calcified plaque burden (CPB).
A total of 292 consecutive tumour patients were examined by whole-body FDG PET and contrast-enhanced CT. The blood pool-corrected standardized uptake value (target to background ratio, TBR) was measured in the LAD, and the contrast-enhanced CT images were used to measure the PFV and the CPB. The Spearman correlation coefficient and the unpaired t test were used for statistical comparison between image-based results and cardiovascular risk factors.
Vascular FDG uptake could be measured for 161 of 292 (55%) patients without myocardial uptake, but the vessel uptake could not be distinguished in the other patients, due to pervasive myocardial uptake. The TBR of the LAD showed significant correlations with hypertension (R = 0.18; p < 0.05), coronary heart disease (R = 0.19; p < 0.05), body mass index (BMI) (R = 0.19; p < 0.05), CPB (R = 0.36; p < 0.001) and PFV (R = 0.20; p < 0.05), but not with other risk factors. Patients with a TBR in the upper tertile had a larger CPB and a higher PFV than patients with a TBR in the lower tertile (9.1 vs 3.5; p < 0.001 for CPB and 92.2 vs 71.5 mm(3); p < 0.05 for PVF).
FDG uptake measurement in the LAD correlates with hypertension, coronary heart disease, BMI, PFV and CPB. However, due to myocardial FDG uptake these measurements are only feasible in one half of the patients.
We measured the uptake of the somatostatin receptor ligand (68)Ga-[1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid]-D-Phe(1),Tyr(3)-octreotate (DOTATATE) in the left anterior descending coronary artery (LAD) in association with calcified plaques (CPs) and cardiovascular risk factors.
Seventy consecutive tumor patients were examined by whole-body (68)Ga-DOTATATE contrast-enhanced PET/CT. Blood-pool-corrected standardized uptake value (target-to-background ratio) was measured in the LAD, and CT images were used to detect CP. Cardiovascular risk factors and history of prior cardiovascular events were recorded.
(68)Ga-DOTATATE uptake was detectable in the LAD of all patients. Target-to-background ratio in the LAD correlated significantly with the presence of CP (R = 0.34; P < 0.01), prior vascular events (R = 0.26; P < 0.05), and male sex (R = 0.29; P < 0.05), whereas CP correlated with these parameters but also with age (R = 0.34; P < 0.01) and hypertension (R = 0.25; P < 0.05).
In a series of oncologic patients, those with prior cardiovascular events and calcified atherosclerotic plaques showed significantly increased (68)Ga-DOTATATE uptake in the LAD, suggesting a potential role of this tracer for plaque imaging in the coronary arteries.
Unlabelled:
Ten percent of humans lack specific binding of [(11)C]PBR28 to 18 kDa translocator protein (TSPO), a biomarker for inflammation. "Non-binders" have not been reported using another TSPO radioligand, [(11)C]-(R)-PK 11195, despite its use for more than two decades. This study asked two questions: (1) What is the cause of non-binding to PBR28? and (2) Why has this phenomenon not been reported using [(11)C]-(R)-PK 11195?
Methods:
Five binders and five non-binders received whole-body imaging with both [(11)C]-(R)-PK 11195 and [(11)C]PBR28. In vitro binding was performed using leukocyte membranes from binders and non-binders and the tritiated versions of the ligand. Rhesus monkeys were imaged with [(11)C]-(R)-PK 11195 at baseline and after blockade of TSPOs.
Results:
Using [(11)C]PBR28, uptake in all five organs with high densities of TSPO (lung, heart, brain, kidney, and spleen) was 50% to 75% lower in non-binders than in binders. In contrast, [(11)C]-(R)-PK 11195 distinguished binders and non-binders in only heart and lung. For the in vitro assay, [(3)H]PBR28 had more than 10-fold lower affinity to TSPO in non-binders than in binders. The in vivo specific binding of [(11)C]-(R)-PK 11195 in monkey brain was approximately 80-fold lower than that reported for [(11)C]PBR28.
Conclusions:
Based on binding of [(3)H]PK 11195 to leukocyte membranes, both binders and non-binders express TSPO. Non-binding to PBR28 is caused by its low affinity for TSPO in non-binders. Non-binding may be differentially expressed in organs of the body. The relatively low in vivo specific binding of [(11)C]-(R)-PK 11195 may have obscured its detection of non-binding in peripheral organs.
Infectious and inflammatory processes, in particular those involving the cardiovascular system, are not a story of the past. New aggressive pathogens are responsible for difficult-to-treat infections. Present-day problems such as diabetes are associated with frequent and at times severe infectious processes, with high morbidity related to the disease or to available therapeutic options. Infections involving the heart or vessels pose clinical challenges in diagnosing and planning the most appropriate therapeutic strategy. Inflammatory processes are diagnosed more frequently today, acknowledged as pathologic conditions of high clinical significance, and much is invested in developing efficient therapeutic options. Nuclear medicine procedures are an important component of the evaluation armamentarium used in patients with suspected or confirmed infectious and inflammatory processes. Their role relies on the strength of noninvasive scintigraphic imaging tests that provide functional and metabolic information early during the course of the disease. Drawbacks of nuclear medicine procedures related to either the use of specific radiolabeled tracers or to their rather low resolution are overcome to a large extent during the last decade by the introduction of hybrid positron emission tomography/computed tomography and single-photon emission computed tomography/computed tomography imaging devices. Initial validated results regarding the role of nuclear medicine and of hybrid imaging using various radiotracers in the evaluation of cardiovascular infections and inflammatory processes are emerging over the last few years. They indicate the potentially important role of these modalities for early and precise diagnosis, in defining the whole extent of disease, for individualized treatment tailoring and for monitoring response to treatment. Attention needs to be given to match the appropriate imaging test and radiolabeled agent to the clinical question at hand. Nuclear medicine in general and hybrid imaging procedures in particular will redefine in future the diagnostic and therapeutic capabilities in patients with suspected or known infections and inflammations of the cardiovascular system.
Vascular prosthesis infection (VPI) is a life-threatening complication that occurs in 0.5-5% of prostheses. Low-grade infections in non-acute patients are a diagnostic challenge requiring a new method with good diagnostic accuracy. The aim of this work was to define the accuracy of (18)F-FDG PET/CT in these settings and to identify essential parameters of the evaluation.
PET/CT was performed prospectively in 76 consecutive patients with a total of 96 vascular prosthetic grafts in which infection was suspected. PET/CT scans were analysed in terms of the presence and intensity of focal and diffuse FDG uptake, the presence of an anastomotic pseudoaneurysm, the presence of an irregular boundary of infiltration, a combination of these, and the uptake ratio between the graft and blood background. The gold standard was based on operative/histopathological finding or a clinical follow up of >6 months.
Among the various assessed parameters only focal FDG uptake and an irregular graft boundary were significant predictors of VPI. Focal intense FDG uptake together with an irregular boundary of the lesion on CT scan predicted VPI with 97% probability, while smooth lesion boundaries and no focal FDG uptake predicted a probability of VPI of less than 5%. Even in lesions with nondiagnostic inhomogeneous focal FDG uptake (18/96) an irregular boundary effectively helped in decision-making with a probability of 28% (smooth) or 77% (irregular) for VPI.
PET/CT gave reliable results with an accuracy >95% in 75% of prostheses. PET/CT can identify those prostheses (25% of prosthesis) for which its diagnostic accuracy is diminished to 70-75%. In our series PET/CT was an excellent diagnostic modality for suspected VPI.
Fever of unknown origin (FUO) is a challenging diagnostic problem. Timely identification and precise localization of the causing process are critical for appropriate patient management. The present prospective study evaluates the role of PET/CT using (18)F-FDG in the investigation of FUO.
A total of 48 consecutive patients (25 men, 23 women; age range, 24-82 y) with FUO underwent (18)F-FDG PET/CT scans. FUO was defined as a fever of more than 38.3 degrees C that lasted for more than 3 wk and failure to reach diagnosis after more than 1 wk of inpatient investigation. The performance of PET/CT for identifying the etiology of FUO was assessed. Final diagnosis was based on histopathology, microbiologic assays, or clinical and imaging follow-up.
PET/CT detected suggestive foci of increased (18)F-FDG uptake in 27 patients. In 22 of these 27 positive studies (81%), PET/CT identified the underlying disease and diagnosed infection in 9 patients, an inflammatory process in 10 patients, and malignancy in 3 patients. (18)F-FDG PET/CT was negative in 21 patients. All these patients were diagnosed as having systemic nonfocal infection or drug-induced fever or showed spontaneous resolution of the febrile state with no further evidence of a localized inflammatory, infectious, or malignant process for a clinical follow-up period of 12-36 mo.
(18)F-FDG PET/CT identified the underlying cause of the fever in 46% of the present study population and contributed to the diagnosis or exclusion of a focal pathologic etiology of the febrile state in 90% of patients. (18)F-FDG PET/CT has a high negative predictive value (100%) for assessment of FUO. If confirmed by further studies, (18)F-FDG PET/CT may be used in the future as an initial noninvasive diagnostic modality for assessment of this group of patients.
Angiogenesis is a critical early feature of atherosclerotic plaque development and may also feature prominently in the pathogenesis of aortic valve stenosis. It has been shown that MRI can detect and quantify specific molecules of interest expressed in cardiovascular disease and cancer by measuring the unique fluorine signature of appropriately targeted perfluorocarbon (PFC) nanoparticles. In this study, we demonstrated specific binding of alphanubeta3 integrin targeted nanoparticles to neovasculature in a rabbit model of aortic valve disease. We also showed that fluorine MRI could be used to detect and quantify the development of neovasculature in the excised aortic valve leaflets.
New Zealand White rabbits consumed a cholesterol diet for ~180 days and developed aortic valve thickening, inflammation, and angiogenesis mimicking early human aortic valve disease. Rabbits (n = 7) were treated with alphanubeta3 integrin targeted PFC nanoparticles or control untargeted PFC nanoparticles (n = 6). Competitive inhibition in vivo of nanoparticle binding (n = 4) was tested by pretreatment with targeted nonfluorinated nanoparticles followed 2 hours later by targeted PFC nanoparticles. 2 hours after treatment, aortic valves were excised and 19F MRS was performed at 11.7T. Integrated 19F spectral peaks were compared using a one-way ANOVA and Hsu's MCB (multiple comparisons with the best) post hoc t test. In 3 additional rabbits treated with alphanubeta3 integrin targeted PFC nanoparticles, 19F spectroscopy was performed on a 3.0T clinical scanner. The presence of angiogenesis was confirmed by immunohistochemistry.
Valves of rabbits treated with targeted PFC nanoparticles had 220% more fluorine signal than valves of rabbits treated with untargeted PFC nanoparticles (p < 0.001). Pretreatment of rabbits with targeted oil-based nonsignaling nanoparticles reduced the fluorine signal by 42% due to competitive inhibition, to a level not significantly different from control animals. Nanoparticles were successfully detected in all samples scanned at 3.0T. PECAM endothelial staining and alphanubeta3 integrin staining revealed the presence of neovasculature within the valve leaflets.
Integrin-targeted PFC nanoparticles specifically detect early angiogenesis in sclerotic aortic valves of cholesterol fed rabbits. These techniques may be useful for assessing atherosclerotic components of preclinical aortic valve disease in patients and could assist in defining efficacy of medical therapies.
During normal tissue remodeling, macrophages remove unwanted cells, including those that have undergone programmed cell death, or apoptosis. This widespread process extends to the deletion of thymocytes (negative selection), in which cells expressing inappropriate Ag receptors undergo apoptosis, and are phagocytosed by thymic macrophages. Although phagocytosis of effete leukocytes by macrophages has been known since the time of Metchnikoff, only recently has it been recognized that apoptosis leads to surface changes that allow recognition and removal of these cells before they are lysed. Our data suggest that macrophages specifically recognize phosphatidylserine that is exposed on the surface of lymphocytes during the development of apoptosis. Macrophage phagocytosis of apoptotic lymphocytes was inhibited, in a dose-dependent manner, by liposomes containing phosphatidyl-L-serine, but not by liposomes containing other anionic phospholipids, including phosphatidyl-D-serine. Phagocytosis of apoptotic lymphocytes was also inhibited by the L isoforms of compounds structurally related to phosphatidylserine, including glycerophosphorylserine and phosphoserine. The membranes of apoptotic lymphocytes bound increased amounts of merocyanine 540 dye relative to those of normal cells, indicating that their membrane lipids were more loosely packed, consistent with a loss of membrane phospholipid asymmetry. Apoptotic lymphocytes were shown to express phosphatidylserine (PS) externally, because PS on their surfaces was accessible to derivatization by fluorescamine, and because apoptotic cells expressed procoagulant activity. These observations suggest that apoptotic lymphocytes lose membrane phospholipid asymmetry and expose phosphatidylserine on the outer leaflet of the plasma membrane. Macrophages then phagocytose apoptotic lymphocytes after specific recognition of the exposed PS.
The accumulation of macrophage foam cells in atherosclerotic lesions is associated with both initiation and progression of this disease. Scavenger receptors CD36 and SRA are the primary receptors responsible for conversion of macrophages into foam cells. Integrin αVβ3 plays a role in the differentiation of several cell types, but its involvement in the transition of macrophages into foam cells and the potential role of this receptor in atherosclerosis have not been examined. Using an in vitro model of single surface receptor activation by binding with an immobilized monoclonal antibody specific to αVβ3 integrin we show that ligation of αVβ3 integrin prevents differentiation of blood monocytes and macrophages into the foam cell phenotype via coordinate down-regulation of CD36 and SRA. This effect of αVβ3 integrin ligation can be reproduced by contact with endothelial cells, whereas the inhibition of αVβ3 receptor ligation restores the uptake of oxidized low-density lipoprotein. Moreover, we found that αVβ3 integrin is readily detected in situ on macrophages in early and advanced atherosclerotic lesions and that in vitro exposure to oxidized low-density lipoprotein up-regulates αVβ3 integrin expression. We hypothesize that αVβ3 integrin regulates macrophage functional maturation into foam cells in a persistent manner, and therefore, by targeting αVβ3 receptor it could potentially be possible to regulate progression of atherosclerosis in humans.
background Calcific aortic stenosis has many characteristics in common with atherosclerosis, in- cluding hypercholesterolemia. We hypothesized that intensive lipid-lowering therapy would halt the progression of calcific aortic stenosis or induce its regression. methods In this double-blind, placebo-controlled trial, patients with calcific aortic stenosis were randomly assigned to receive either 80 mg of atorvastatin daily or a matched placebo. Aortic-valve stenosis and calcification were assessed with the use of Doppler echocardi- ography and helical computed tomography, respectively. The primary end points were change in aortic-jet velocity and aortic-valve calcium score. results Seventy-seven patients were assigned to atorvastatin and 78 to placebo, with a median follow-up of 25 months (range, 7 to 36). Serum low-density lipoprotein cholesterol concentrations remained at 130±30 mg per deciliter in the placebo group and fell to 63±23 mg per deciliter in the atorvastatin group (P
Purpose:
Early detection of infectious endocarditis is challenging. For diagnosing infectious endocarditis, the revised Duke criteria are the gold standard. Evidence of endocardial involvement on echocardiography is a major criterion, but sensitivity and specificity of echocardiography are not optimal. Here we investigated the utility of (18)F-fluorodeoxyglucose (FDG) positron emission tomography and computed tomography (PET/CT) to diagnose infectious endocarditis in patients with gram-positive bacteraemia.
Methods:
Seventy-two patients with gram-positive bacteraemia were prospectively included. Patients with a positive blood culture growing Staphylococcus aureus, Streptococcus species or Enterococcus species were eligible when a risk factor for developing metastatic infectious foci was present. Infectious endocarditis was defined according to the revised Duke criteria. All patients underwent (18)F-FDG PET/CT and echocardiography. (18)F-FDG uptake in or around the heart valves was evaluated independently by two nuclear medicine physicians.
Results:
Sensitivity for diagnosing infectious endocarditis with (18)F-FDG PET/CT was 39% and specificity was 93%. The positive predictive value was 64% and negative predictive value was 82%. The mortality rate in patients without infectious endocarditis and without increased (18)F-FDG uptake in or around the heart valves was 18%, and in patients without infectious endocarditis but with high (18)F-FDG uptake in or around the heart valves the mortality rate was 50% (p = 0.181).
Conclusion:
(18)F-FDG PET/CT is currently not sufficiently adequate for the diagnosis of infectious endocarditis because of its low sensitivity. Improvements such as patient preparation with low carbohydrate-fat allowed diet and technical advances in the newest PET/CT scanners may increase sensitivity in future studies.
Unlabelled:
The objective of this study was to evaluate extraaortic arterial (18)F-FDG accumulation in asymptomatic cohorts by sex and to clarify the association between extraaortic arterial (18)F-FDG accumulation and cardiovascular risk factors (CRFs) and coronary artery stenosis (CAS).
Methods:
Five hundred twenty-one asymptomatic individuals (351 men and 170 women) who underwent cancer and CAS screening were enrolled. We evaluated extraaortic arterial (18)F-FDG accumulation in the carotid artery (CA) and iliofemoral artery (IFA) and classified the accumulation patterns into 3 types. Type 1 patients had no extraaortic arterial (18)F-FDG accumulation, type 2 had accumulation in either the CA or the IFA, and type 3 had accumulation in both the CA and IFA. CRFs (age, low-density lipoprotein [LDL] and high-density lipoprotein [HDL] cholesterol, triglyceride concentration, visceral abdominal fat, hypertension, diabetes, and smoking) and significant CAS were examined in relation to each accumulation type.
Results:
The men showed more extensive extraaortic arterial (18)F-FDG accumulation than the women. Type 3 accumulation (60.4% vs. 37.1%, P < 0.0001) was more frequently observed in men, whereas type 2 (34.2% vs. 44.7%, P = 0.02) and type 1 (5.4% vs. 18.2%, P < 0.0001) accumulation were more frequent in women. The CRFs other than smoking tended to be worse with extensive extraaortic arterial (18)F-FDG accumulation. A multivariate logistic regression analysis showed that hypertension, age, LDL cholesterol, triglyceride, and visceral abdominal fat were significantly associated with type 3 accumulation in men, and LDL cholesterol and HDL cholesterol (inversely) were significantly associated with type 3 accumulation in women. CAS was found in 4.2% (9/212) of male patients and in 1.6% (1/63) of female patients with type 3 accumulation, whereas no CAS was found in the other 2 types.
Conclusion:
The men showed more extensive extraaortic arterial (18)F-FDG accumulation than the women. LDL cholesterol was associated with extensive extraaortic arterial (18)F-FDG accumulation in both sexes, but the other CRFs associated with extensive extraaortic (18)F-FDG arterial accumulation differed between the sexes. The type 3 accumulation was considered to pose a risk of CAS, especially in male patients, whereas non-type 3 accumulation presented little risk.
Imaging plays a fundamental role in the current diagnosis and treatment of valvular heart disease (VHD) and in the preclinical and clinical research aiming at the development of novel pharmacologic or interventional therapies. Doppler echocardiography remains the primary imaging technique for the clinical management of VHD. However, the multifaceted and complex nature of VHD and the rapid development of transcatheter valve therapies has led to a spectacular increase in the use of multimodality imaging in the past decade. The purpose of this article is to review the current and emerging roles of the different imaging modalities in the diagnosis and treatment of VHD and to present the new directions for future research and clinical applications.
In recent years, molecular imaging with positron emission tomography (PET) and more recently, PET coupled with computed tomography (CT) have made a valuable impact in various clinical arenas, primarily within the field of oncology, but also in cardiovascular medicine, particularly in detecting coronary artery disease and myocardial viability. More recently, PET imaging has been proven useful in the diagnosis and evaluation of inflammation and infection at different organ sites. Application of PET in the case of Infective Endocarditis (IE) is still in its infancy and indeed the value of this application in the detection of vegetations is debated primarily due to sensitivity issues of the tracer in cardiac tissue and small vegetations. Interestingly, however, reports are now emerging highlighting the role that this application has played in the diagnosis, assessment of complications such as emboli and metastatic infection and the monitoring of therapeutic treatment of IE. More recently, PET/CT has proven valuable in the diagnosis and assessment of cardiac implantable electronic device (CIED)-related infection and its use has highlighted the contribution that this imaging modality may play in assessing the need for surgery in patients with such infections. This article reviews the literature with regard to the potential value of 2-deoxy-2-[(18)F]fluoro-D-glucose ((18)FDG)-PET, as well as the pitfalls and limitations of this imaging modality, in relation to cardiac infection. The emerging role (18)FDG-PET/CT has in the diagnosis and monitoring of IE, particularly prosthetic valve IE and CIED-related infections should be considered, particularly in difficult cases.
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 [(11)C]-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.
Objective. – Recent studies have suggested that valvular calcification in calcific aortic stenosis (AS) may be actively regulated. “Receptor Activator of Nuclear factor κB Ligand” (RANKL) and osteoprotegerin (OPG) are members of a cytokine system involved in bone turnover and vascular calcification. Their role in calcific AS is not known.Methods and Results. – By immunohistochemistry using human aortic valves, RANKL was not expressed at relevant levels in controls but detectable in AS. OPG expression was marked in controls but significantly lower in AS. Areas containing focal calcification exhibited significantly less OPG-positive cells as compared to non-calcified regions. Stimulation with RANKL lead to a significant rise in matrix calcification, nodule formation, alkaline phosphatase activity, expression of the bone-type isoenzyme of alkaline phosphatase, and expression of osteocalcin in cultured human aortic valve myofibroblasts. Moreover, RANKL increased DNA binding of the essential osteoblast transcription factor cbfa-1.Conclusion. – RANKL and OPG are differentially expressed in calcific AS. In cultured human aortic valve myofibroblasts, RANKL promotes matrix calcification and induces the expression of osteoblast-associated genes, indicating a transition towards an osteogenic phenotype. These results suggest that the RANKL-OPG pathway may regulate valvular calcification in calcific AS?
Although aortic stenosis is a common condition associated with major morbidity, mortality, and health economic costs, there are currently no medical interventions capable of delaying or halting its progression. Re-evaluation of the underlying pathophysiology is therefore required so that novel therapeutic strategies can be developed. Aortic stenosis is characterized by progressive aortic valve narrowing and secondary left ventricular hypertrophy. Both processes are important because in combination they drive the development of symptoms and adverse events that characterize the latter stages of the disease. In this review, the authors examine the pathophysiology of aortic stenosis with respect to both the valve and the myocardium. In particular, the authors focus on the role of inflammation, fibrosis, and calcification in progressive valve narrowing and then examine the development of left ventricular hypertrophy, its subsequent decompensation, and the transition to heart failure. Finally the authors discuss potential therapeutic strategies on the basis of similarities aortic stenosis shares with other pathological conditions.
Background:
Inflammation following acute myocardial infarction (MI) has detrimental effects on reperfusion, myocardial remodelling, and ventricular function. Magnetic resonance imaging using ultrasmall superparamagnetic particles of iron oxide can detect cellular inflammation in tissues, and we therefore explored their role in acute MI in humans.
Methods and results:
Sixteen patients with acute ST-segment elevation MI were recruited to undergo 3 sequential magnetic resonance scans within 5 days of admission at baseline, 24 and 48 hours following no infusion (controls; n=6) or intravenous infusion of ultrasmall superparamagnetic particles of iron oxide (n=10; 4 mg/kg). T2*-weighted multigradient-echo sequences were acquired and R2* values were calculated for specific regions of interest. In the control group, R2* values remained constant in all tissues across all scans with excellent repeatability (bias of -0.208 s(-1), coefficient of repeatability of 26.96 s(-1); intraclass coefficient 0.989). Consistent with uptake by the reticuloendothelial system, R2* value increased in the liver (84±49.5 to 319±70.0 s(-1); P<0.001) but was unchanged in skeletal muscle (54±8.4 to 67.0±9.5 s(-1); P>0.05) 24 hours after administration of ultrasmall superparamagnetic particles of iron oxide. In the myocardial infarct, R2* value increased from 41.0±12.0 s(-1) (baseline) to 155±45.0 s(-1) (P<0.001) and 124±35.0 s(-1) (P<0.05) at 24 and 48 hours, respectively. A similar but lower magnitude response was seen in the remote myocardium, where it increased from 39±3.2 s(-1) (baseline) to 80±14.9 s(-1) (P<0.001) and 67.0±15.7 s(-1) (P<0.05) at 24 and 48 hours, respectively.
Conclusions:
Following acute MI, uptake of ultrasmall superparamagnetic particles of iron oxide occurs with the infarcted and remote myocardium. This technique holds major promise as a potential method for assessing cellular myocardial inflammation and left ventricular remodelling, which may have a range of applications in patients with MI and other inflammatory cardiac conditions.
Over the last several decades, basic cardiovascular research has significantly enhanced our understanding of pathobiological processes leading to formation, progression, and complications of atherosclerotic plaques. By harnessing these advances in cardiovascular biology, imaging has advanced beyond its traditional anatomical domains to a tool that permits probing of particular molecular structures to image cellular behaviour and metabolic pathways involved in atherosclerosis. From the nascent atherosclerotic plaque to the death of inflammatory cells, several potential molecular and micro-anatomical targets for imaging with particular selective imaging probes and with a variety of imaging modalities have emerged from preclinical and animal investigations. Yet, substantive barriers stand between experimental use and wide clinical application of these novel imaging strategies. Each of the imaging modalities described herein faces hurdles-for example, sensitivity, resolution, radiation exposure, reproducibility, availability, standardization, or costs. This review summarizes the published literature reporting on functional imaging of vascular inflammation in atherosclerotic plaques emphasizing those techniques that have the greatest and/or most immediate potential for broad application in clinical practice. The prospective evaluation of these techniques and standardization of protocols by multinational networks could serve to determine their added value in clinical practice and guide their development and deployment.
Symptomatic carotid stenosis is associated with a 3-fold risk of early stroke recurrence compared to other stroke subtypes. Current carotid imaging techniques rely on estimating plaque-related lumen narrowing but do not evaluate intraplaque inflammation, a key mediator of plaque rupture and thromboembolism. Using combined (18) F-fluorodeoxyglucose positron-emission tomography (FDG-PET)/computed tomography, we investigated the relation between inflammation-related FDG uptake and stroke recurrence.
Consecutive patients with a recent (median, 6.5 days; interquartile range, 4-8) stroke, transient ischemic attack (TIA), or retinal embolism and ipsilateral carotid stenosis (≥50%) were included. FDG uptake was quantified as mean standardized uptake values (SUVs, g/ml). Patients were followed prospectively for stroke recurrence.
Sixty patients were included (25 stroke, 29 TIA, 6 retinal embolism). Twenty-two percent (13 of 60) had stroke recurrence within 90 days. FDG uptake in ipsilateral carotid plaque was greater in patients with early recurrent stroke (mean SUV, 1.85 g/ml; standard deviation [SD], 0.44 vs 1.58 g/ml; SD, 0.32, p = 0.02). On life-table analysis, 90-day recurrence rates with mean SUV greater than a 2.14 g/ml threshold were 80% (95% confidence interval [CI], 41.8-99.2) versus 22.9% (95% CI, 12.3-40.3) with SUV ≤2.14 g/ml (log-rank, p < 0.0001). In a Cox regression model including age and degree of stenosis (50-69% or ≥70%), mean plaque FDG uptake was the only independent predictor of stroke recurrence (adjusted hazard ratio, 6.1; 95% CI, 1.3-28.8; p = 0.02).
In recently symptomatic carotid stenosis, inflammation-related FDG uptake was associated with early stroke recurrence, independent of the degree of stenosis. Plaque FDG-PET may identify patients at highest risk for stroke recurrence, who may be selected for immediate revascularization or intensive medical treatment.
Aortic valve stenosis progression rate is highly variable among patients and to date remains unpredictable. Evaluation of osteoblastic activity inside aortic valves may help identify patients with fast aortic stenosis progression rates and worse prognoses. Fluoride-18 sodium (FNa) is a clinically approved positron emission tomographic (PET) radiotracer with high and rapid bone uptake. The aim of this study was to test whether FNa accumulates in degenerative aortic valves and can be detected with PET imaging. Five patients with severe aortic stenosis and 10 patients free of aortic valvular calcium on computed tomography underwent PET imaging 40 minutes after the injection of 4 MBq/kg of FNa for oncologic or rheumatologic purposes. Maximal standard uptake values (SUVs) were measured retrospectively in aortic valves using PET imaging. Tissue-to-background ratios were calculated for each patient by dividing the maximal SUV measured in aortic valves by the mean SUV of blood. In patients with severe aortic stenosis, an intense accumulation of FNa was detected in aortic valve region on PET imaging, whereas only low activity was found in patients free of valvular calcification (median maximal SUV 2.6 g/ml/kg [interquartile range (IQR) 2.3 to 3.6] vs 2.0 g/ml/kg [IQR 1.7 to 2.2] and median tissue-to-background ratio 2.2 [IQR 2.0 to 2.7] vs 1.5 [IQR 1.5 to 1.7], respectively, p = 0.008 for both). Intraobserver variability for maximal SUV and tissue-to-background ratio in aortic valves was measured at 0.99 and interobserver variability at 0.98 and 0.97, respectively. In conclusion, in this pilot study, FNa accumulated in patients with severe aortic stenosis and could be quantified on PET imaging with good reproducibility. FNa PET imaging represents a promising imaging modality to evaluate osteoblastic activity inside calcified aortic valves.
Rubidium-82 ((82)Rb), the currently commercially available radiotracer for positron emission tomography (PET) myocardial perfusion imaging (MPI), has led to wide availability of PET-MPI for stress-rest imaging. Compared to SPECT MPI, myocardial perfusion PET images have higher spatial and contrast resolution, are less affected by radiotracer scatter, benefit from more precise attenuation correction, and allow dynamic first pass imaging. In addition, PET imaging allows assessment of myocardial function at peak stress and measurement of absolute myocardial blood flow, thus providing critical data not available with SPECT imaging. Further enhancements of the high quality of PET perfusion images may be realized by technologies under development such as respiratory gating, combined respiratory, and ECG gating to generate "motion-frozen" cardiac images, automated patient motion correction software, and high-definition PET, which reduces distortions introduced by the circular geometry of the scanner. Early studies indicate that the experimental PET radiopharmaceutical flurpiridaz F 18 provides high-quality, high-resolution myocardial perfusion images that may enable improved clinical MPI, and has properties well suited to optimized performance by application of these quantitative analytic technologies.
Cardiac hybrid imaging combines different imaging modalities in a way where both modalities equally contribute to image information. Hybrid positron emission tomography-computed tomography (PET-CT) imaging is a promising tool for evaluation of coronary artery disease (CAD) because it enables detection of coronary atherosclerotic lesions by CT angiography and their consequences on myocardial blood flow by PET perfusion in a single study. This appears to offer superior diagnostic accuracy in patients with intermediate risk for CAD compared with stand-alone imaging. Novel, commercially available hybrid scanners containing PET and magnetic resonance as well as development of targeted probes to evaluate molecular and cellular disease mechanisms are expected to provide many new applications for cardiac hybrid imaging. This article focuses on the advantages of cardiac hybrid imaging in the detection of CAD in light of currently available clinical data and discusses the potential future applications.
The pathophysiology of aortic stenosis is incompletely understood, and the relative contributions of valvular calcification and inflammation to disease progression are unknown.
Patients with aortic sclerosis and mild, moderate, and severe stenosis were compared prospectively with age- and sex-matched control subjects. Aortic valve severity was determined by echocardiography. Calcification and inflammation in the aortic valve were assessed by 18F-sodium fluoride (18F-NaF) and 18F-fluorodeoxyglucose (18F-FDG) uptake with the use of positron emission tomography. One hundred twenty-one subjects (20 controls; 20 aortic sclerosis; 25 mild, 33 moderate, and 23 severe aortic stenosis) were administered both 18F-NaF and 18F-FDG. Quantification of tracer uptake within the valve demonstrated excellent interobserver repeatability with no fixed or proportional biases and limits of agreement of ±0.21 (18F-NaF) and ±0.13 (18F-FDG) for maximum tissue-to-background ratios. Activity of both tracers was higher in patients with aortic stenosis than in control subjects (18F-NaF: 2.87±0.82 versus 1.55±0.17; 18F-FDG: 1.58±0.21 versus 1.30±0.13; both P<0.001). 18F-NaF uptake displayed a progressive rise with valve severity (r(2)=0.540, P<0.001), with a more modest increase observed for 18F-FDG (r(2)=0.218, P<0.001). Among patients with aortic stenosis, 91% had increased 18F-NaF uptake (>1.97), and 35% had increased 18F-FDG uptake (>1.63). A weak correlation between the activities of these tracers was observed (r(2)=0.174, P<0.001).
Positron emission tomography is a novel, feasible, and repeatable approach to the evaluation of valvular calcification and inflammation in patients with aortic stenosis. The frequency and magnitude of increased tracer activity correlate with disease severity and are strongest for 18F-NaF.
http://www.clinicaltrials.gov. Unique identifier: NCT01358513.
The authors aimed to develop an image-based registration scheme to detect and correct patient motion in stress and rest cardiac positron emission tomography (PET)/CT images. The patient motion correction was of primary interest and the effects of patient motion with the use of flurpiridaz F 18 and (82)Rb were demonstrated.
The authors evaluated stress/rest PET myocardial perfusion imaging datasets in 30 patients (60 datasets in total, 21 male and 9 female) using a new perfusion agent (flurpiridaz F 18) (n = 16) and (82)Rb (n = 14), acquired on a Siemens Biograph-64 scanner in list mode. Stress and rest images were reconstructed into 4 ((82)Rb) or 10 (flurpiridaz F 18) dynamic frames (60 s each) using standard reconstruction (2D attenuation weighted ordered subsets expectation maximization). Patient motion correction was achieved by an image-based registration scheme optimizing a cost function using modified normalized cross-correlation that combined global and local features. For comparison, visual scoring of motion was performed on the scale of 0 to 2 (no motion, moderate motion, and large motion) by two experienced observers.
The proposed registration technique had a 93% success rate in removing left ventricular motion, as visually assessed. The maximum detected motion extent for stress and rest were 5.2 mm and 4.9 mm for flurpiridaz F 18 perfusion and 3.0 mm and 4.3 mm for (82)Rb perfusion studies, respectively. Motion extent (maximum frame-to-frame displacement) obtained for stress and rest were (2.2 ± 1.1, 1.4 ± 0.7, 1.9 ± 1.3) mm and (2.0 ± 1.1, 1.2 ±0 .9, 1.9 ± 0.9) mm for flurpiridaz F 18 perfusion studies and (1.9 ± 0.7, 0.7 ± 0.6, 1.3 ± 0.6) mm and (2.0 ± 0.9, 0.6 ± 0.4, 1.2 ± 1.2) mm for (82)Rb perfusion studies, respectively. A visually detectable patient motion threshold was established to be ≥2.2 mm, corresponding to visual user scores of 1 and 2. After motion correction, the average increases in contrast-to-noise ratio (CNR) from all frames for larger than the motion threshold were 16.2% in stress flurpiridaz F 18 and 12.2% in rest flurpiridaz F 18 studies. The average increases in CNR were 4.6% in stress (82)Rb studies and 4.3% in rest (82)Rb studies.
Fully automatic motion correction of dynamic PET frames can be performed accurately, potentially allowing improved image quantification of cardiac PET data.
We sought to determine whether intraplaque inflammation could be measured with positron emission tomography/computed tomography angiography (PET/CTA) using (11)C-PK11195, a selective ligand of the translocator protein (18 kDa) (TSPO) which is highly expressed by activated macrophages.
Patients (n = 32; mean age 70 ± 9 years) with carotid stenoses (n = 36; 9 symptomatic and 27 asymptomatic) underwent (11)C-PK11195 PET/CTA imaging. (11)C-PK11195 uptake into carotid plaques was measured using target-to-background ratios (TBR). On CTA images, plaque composition was assessed by measuring CT attenuation of the carotid plaque. Eight patients underwent carotid endarterectomy and ultrathin contiguous sections were processed for TSPO and CD68 (using immunohistochemical staining, (3)H-PK11195 autoradiography, and confocal fluorescence microscopy). Carotid plaques associated with ipsilateral symptoms (stroke or transient ischaemic attack) had higher TBR (1.06 ± 0.20 vs. 0.86 ± 0.11, P = 0.001) and lower CT attenuation [(median, inter-quartile range) 37, 24-40 vs. 71, 56-125 HU, P = 0.01] than those without. On immunohistochemistry and confocal fluorescence microscopy, CD68 and PBR co-localized with (3)H-PK11195 uptake at autoradiography. There was a significant correlation between (11)C-PK11195 TBR and autoradiographic percentage-specific binding (r = 0.77, P = 0.025). Both TBR and CT plaque attenuation had high negative predictive values (91 and 92%, respectively) for detecting symptomatic patients. However, the best positive predictive value (100%) was achieved when TBR and CT attenuation were combined.
Imaging intraplaque inflammation in vivo with (11)C-PK11195 PET/CTA is feasible and can distinguish between recently symptomatic and asymptomatic plaques. Patients with a recent ischaemic event had ipsilateral plaques with lower CT attenuation and increased (11)C-PK11195 uptake.
The goal of this study was to assess the prognostic significance of midwall and infarct patterns of late gadolinium enhancement (LGE) in aortic stenosis.
Myocardial fibrosis occurs in aortic stenosis as part of the hypertrophic response. It can be detected by LGE, which is associated with an adverse prognosis in a range of other cardiac conditions.
Between January 2003 and October 2008, consecutive patients with moderate or severe aortic stenosis undergoing cardiovascular magnetic resonance with administration of gadolinium contrast were enrolled into a registry. Patients were categorized into absent, midwall, or infarct patterns of LGE by blinded independent observers. Patient follow-up was completed using patient questionnaires, source record data, and the National Strategic Tracing Service.
A total of 143 patients (age 68 ± 14 years; 97 male) were followed up for 2.0 ± 1.4 years. Seventy-two underwent aortic valve replacement, and 27 died (24 cardiac, 3 sudden cardiac deaths). Compared with those with no LGE (n = 49), univariate analysis revealed that patients with midwall fibrosis (n = 54) had an 8-fold increase in all-cause mortality despite similar aortic stenosis severity and coronary artery disease burden. Patients with an infarct pattern (n = 40) had a 6-fold increase. Midwall fibrosis (hazard ratio: 5.35; 95% confidence interval: 1.16 to 24.56; p = 0.03) and ejection fraction (hazard ratio: 0.96; 95% confidence interval: 0.94 to 0.99; p = 0.01) were independent predictors of all-cause mortality by multivariate analysis.
Midwall fibrosis was an independent predictor of mortality in patients with moderate and severe aortic stenosis. It has incremental prognostic value to ejection fraction and may provide a useful method of risk stratification.
The present review provides an overview of the role of cardiac positron emission tomography in the diagnosis and management of cardiovascular disease. It expands on the relative advantages and disadvantages over other imaging modalities as well as the available evidence supporting its value in the diagnosis and management of patients with coronary artery disease, the assessment of myocardial viability, and evaluation of the cardiac sympathetic nervous system. Furthermore, the recent developments, such as the implementation of high-end computed tomography devices to form hybrid systems, and the advances of molecular imaging probes in experimental applications are briefly discussed.
This review concentrates on the latest advances in molecular imaging technology, including PET, MRI, and optical imaging. In PET, significant improvements in tumor detection and image resolution have been achieved by introducing new scintillation materials, iterative image reconstruction, and correction methods. These advances enabled the first clinical scanners capable of time-of-flight detection and incorporating point-spread-function reconstruction to compensate for depth-of-interaction effects. In the field of MRI, the most important developments in recent years have mainly been MRI systems with higher field strengths and improved radiofrequency coil technology. Hyperpolarized imaging, functional MRI, and MR spectroscopy provide molecular information in vivo. A special focus of this review article is multimodality imaging and, in particular, the emerging field of combined PET/MRI.
Because fluorodeoxyglucose positron emission tomography (FDG-PET) imaging provides a noninvasive index of inflammation, we sought to assess whether FDG uptake in the aortic valve (AV) is increased in aortic stenosis (AS).
AS is associated with valvular inflammation.
FDG-PET/computed tomography data were retrospectively evaluated in 84 patients (age 73 ± 9 years, 45% female), 42 patients with AS, and 42 age-matched controls. FDG uptake was determined within the AV while blinded to AS severity. Target-to-background ratio (TBR) was calculated as valvular/blood activity. Stenosis severity was established on echocardiography, and presence of AV calcification was independently assessed on computed tomography.
The aortic valve PET signal (TBR) was increased in AS compared with controls (median 1.53 [interquartile range (IQR): 1.42 to 1.76] vs. 1.34 [IQR: 1.20 to 1.55]; p < 0.001). Further, compared with controls, TBR was increased in mild (median 1.50 [IQR: 1.36 to 1.75]; p = 0.01) and moderate (median 1.70 [IQR: 1.52 to 1.94]; p < 0.001), but not in severe AS (median 1.49 [IQR: 1.40 to 1.54]; p = 0.08). When subjects were categorized according to AV calcification, valvular FDG uptake was increased in mildly (median 1.50 [IQR: 1.36 to 1.79]; p < 0.01) and moderately (median 1.67 [IQR: 1.50 to 1.85]; p < 0.001), but not severely calcified valves (median 1.51 [IQR: 1.38 to 1.54]; p = 0.15), compared with noncalcified valves (median 1.35 [IQR: 1.20 to 1.52]).
This study supports the hypothesis that AS is an inflammatory condition and suggests that inflammation may be reduced in late-stage disease. This may have important implications in the design of studies assessing the effect of therapeutic agents in modifying progression of AS.
The purpose of this study was to assess the impact on cardiovascular and adverse events of attaining low-density lipoprotein cholesterol (LDL-C) levels <50 mg/dl with rosuvastatin in apparently healthy adults in the JUPITER (Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin) trial.
The safety and magnitude of cardiovascular risk reduction conferred by treatment to LDL-C levels below current recommended targets remain uncertain.
A cohort of 17,802 apparently healthy men and women with high-sensitivity C-reactive protein ≥2 mg/l and LDL-C <130 mg/dl were randomly allocated to rosuvastatin 20 mg daily or placebo, and followed up for all-cause mortality, major cardiovascular events, and adverse events. In a post-hoc analysis, participants allocated to rosuvastatin were categorized as to whether or not they had a follow-up LDL-C level <50 mg/dl.
During a median follow-up of 2 years (range up to 5 years), rates of the primary trial endpoint were 1.18, 0.86, and 0.44 per 100 person-years in the placebo group (n = 8,150) and rosuvastatin groups without LDL-C <50 mg/dl (n = 4,000) or with LDL-C <50 mg/dl (n = 4,154), respectively (fully-adjusted hazard ratio: 0.76; 95% confidence interval: 0.57 to 1.00 for subjects with no LDL-C <50 mg/dl vs. placebo and 0.35, 95% confidence interval: 0.25 to 0.49 for subjects attaining LDL-C <50 mg/dl; p for trend <0.0001). For all-cause mortality, corresponding event rates were 0.67, 0.65, and 0.39 (p for trend = 0.004). Rates of myalgia, muscle weakness, neuropsychiatric conditions, cancer, and diabetes mellitus were not significantly different among rosuvastatin-allocated participants with and without LDL-C <50 mg/dl.
Among adults with LDL-C <130 mg/dl and high-sensitivity C-reactive protein ≥2 mg/l, rosuvastatin-allocated participants attaining LDL-C <50 mg/dl had a lower risk of cardiovascular events without a systematic increase in reported adverse events.
Mitral annular calcification (MAC) has been suggested as a reliable, time-averaged marker of atherosclerosis and is associated with coronary artery disease, heart failure, ischemic stroke, and increased mortality. Data on the relationship between MAC and cardiovascular morbidity and mortality in atrial fibrillation (AF) are sparse, with the exception of the relationship between MAC and stroke. We investigated the association of MAC with cardiovascular morbidity, stroke, cardiovascular mortality, and all-cause death in a cohort of middle-aged patients with AF with a mean 10-year follow-up.
This was an observational study of patients with nonvalvular AF between 1992 and 2007.
Of 1,056 patients, 33 (3.1%) had MAC; they were more likely to be older and female and to have a dilated left atrium, reduced left ventricular ejection fraction, permanent AF, hypertension, and/or diabetes mellitus (all P < .05). Total follow-up was 10,418.5 years (mean, 9.9 ± 5.9 years), and the mean age was 52.7 ± 12.2 years. In univariate analysis, MAC was associated with all-cause death, cardiovascular death, stroke, new cardiac morbidity (all P < .05), and the composite end point of ischemic stroke, myocardial infarction (MI), and all-cause death (P < .001). In multivariate analyses, MAC was related to all-cause death (hazard ratio [HR], 4.3; 95% CI, 1.8-10.0; P < .001), cardiovascular death (HR, 3.5; 95% CI, 1.2-10.4; P = .025), the composite end point (HR, 2.1; 95% CI, 1.0-4.3; P = .048), and new cardiac morbidity (HR, 2.4; 95% CI, 1.3-4.5; P = .005). There was no significant relationship between MAC and stroke or MI in the multivariate analyses.
MAC is associated with increased cardiovascular morbidity, cardiovascular mortality, and all-cause mortality of patients with AF. MAC should be acknowledged as a marker of increased cardiovascular risk in middle-aged patients with AF.
Angiogenesis plays an important role in the pathophysiology of atherosclerosis and after myocardial infarction. Furthermore, angiogenesis has been the focus of many therapeutic strategies. In view of that, a direct and clear understanding of the role of these pathways in the living subject is needed. Molecular Imaging has emerged as a powerful tool to study biological processes non-invasively. In this review, evidence will be presented and discussed on the feasibility of different molecular imaging strategies to study the involvement of angiogenic pathways in the assessment of the atherosclerotic disease and as a tool to assess angiogenic therapy. Focus will be placed on those imaging modalities with the potential to be translated to clinical use.
The pathobiology of aortic stenosis (AS) now is recognized to have many similiarities to that of atherosclerosis, a disease in which lipid lowering therapy with statin drugs has been successful. Accordingly statins have been used to attempt to retard the progression of AS with variable success. The SEAS trial compared the effects of the combination of simvastatin and ezetimibe to placebo in retarding the progression of aortic stenosis (AS) and was the largest randomized trial of such therapies. One thousand eight hundred seventy three patients with moderate AS were included. The group receiving the drugs had a large reduction in LDL cholesterol and a reduction in coronary events. However drug therapy had no effect on the progression of AS. Conclusion. While AS has many similarities to atherosclerosis, lipid lowering therapy does not affect progression of moderate to severe AS.
In the acute setting of endocarditis it is very important to assess both the vegetation itself, as well as potential life-threatening complications, in order to decide whether antibiotic therapy will be sufficient or urgent surgery is indicated. A single whole-body scan investigating inflammatory changes could be very helpful to achieve a swift and efficient assessment.
In this study we assessed whether (18)F-FDG can be used to detect and localize peripheral embolism or distant infection. Twenty-four patients with 25 episodes of endocarditis, enrolled between March 2006 and February 2008, underwent (18)F-FDG PET/CT imaging on a dedicated PET/CT scanner.
PET/CT imaging revealed a focus of peripheral embolization and/or metastatic infection in 11 episodes (44%). One episode had a positive PET/CT scan result for both embolism and metastatic infection. PET/CT detected seven positive cases (28%) in which there was no clinical suspicion. Valve involvement of endocarditis was seen only in three patients (12%).
PET/CT may be an important diagnostic tool for tracing peripheral embolism and metastatic infection in the acute setting of infective endocarditis, since a PET/CT scan detected a clinically occult focus in nearly one third of episodes.
Aortic stenosis (AS) is an active process with similarities to atherosclerosis. The objective of this study was to assess the effect of cholesterol lowering with rosuvastatin on the progression of AS.
This was a randomized, double-blind, placebo-controlled trial in asymptomatic patients with mild to moderate AS and no clinical indications for cholesterol lowering. The patients were randomized to receive either placebo or rosuvastatin 40 mg daily. A total of 269 patients were randomized: 134 patients to rosuvastatin 40 mg daily and 135 patients to placebo. Annual echocardiograms were performed to assess AS progression, which was the primary outcome; the median follow-up was 3.5 years. The peak AS gradient increased in patients receiving rosuvastatin from a baseline of 40.8+/-11.1 to 57.8+/-22.7 mm Hg at the end of follow-up and in patients with placebo from 41.6+/-10.9 mm Hg at baseline to 54.8+/-19.8 mm Hg at the end of follow-up. The annualized increase in the peak AS gradient was 6.3+/-6.9 mm Hg in the rosuvastatin group and 6.1+/-8.2 mm Hg in the placebo group (P=0.83). Treatment with rosuvastatin was not associated with a reduction in AS progression in any of the predefined subgroups.
Cholesterol lowering with rosuvastatin 40 mg did not reduce the progression of AS in patients with mild to moderate AS; thus, statins should not be used for the sole purpose of reducing the progression of AS. Clinical Trial Registration Information- URL: http://www.controlled-trials.com/. Clinical trial registration number: ISRCTN 32424163.
To review the literature on diagnostic accuracy and clinical value of single-photon emission computed tomography (SPECT) and positron emission tomography (PET) for imaging of bone and joint infections.
The PubMed/MEDLINE and Embase (OvidSP) literature databases were systematically searched for publications on SPECT and PET on osteomyelitis and prosthetic bone and joint infections using specific guidelines with MeSH-terms, truncations, and completion using cross-references.
In 44 original articles (15 for SPECT and 29 for (18)F-fluorodeoxyglucose [FDG]-PET) on osteomyelitis and prosthetic bone and joint infection, 1634 patients were included (580 patients SPECT, 1054 patients FDG-PET). Level of evidence (Oxford criteria) was 2-3b. For SPECT, the highest diagnostic accuracy of 95% for diagnosis of bone and joint infections is achieved with combined (111)In-WBC and (99m)Tc-sulfur colloid. Acceptable diagnostic accuracy was also obtained with (99m)Tc-WBC or (111)In-WBC combined with (99m)Tc-methylene diphosphonate ((99m)Tc-MDP). FDG-PET is useful for diagnosis of osteomyelitis with a sensitivity and specificity generally over 95%. In patients with orthopedic implant infections, sensitivity varies widely from 28% to 91% and specificity from 9% to 97%. This variation in FDG-PET performance in orthopedic implant infections depends largely on the (use of different) criteria to diagnose infection. Determination of the best criteria is still a matter of debate.
SPECT/computed tomography (CT) with (111)In-WBC combined with (99m)Tc-MDP or (99m)Tc-sulfur colloid seems to be the best imaging technique for diagnosis of bone and joint infections. FDG-PET is also useful for diagnosis of osteomyelitis with improved spatial resolution over SPECT imaging, allowing more accurate localization. Localization can be further improved by adding CT. Diagnosis of orthopedic implant infections with FDG-PET depends strongly on the localization of the implant and the criteria used to diagnose infection. Confirmation of well defined criteria to diagnose infection on FDG-PET in patients with metallic implants is thus of paramount importance for optimal diagnosis.
A patient with postvascular graft placement presented with bacteremia but no localizing symptoms. Our standard infected graft workup of computed tomography (CT) scan, ultrasound scan, magnetic resonance imaging (MRI) scan, and additional laboratory tests did not localize the infection source. Nuclear medicine had three options including white blood cell (WBC) scan, gallium scan, and the fluorine-18-fluorodeoxyglucose positron emission tomography (FDG-PET)/CT scan. FDG-PET/CT imaging alone demonstrated the location. We present an unusual case of Mycobacterium abscessus in a vascular graft not localized with CT scan, ultrasound scan, or MRI scan and could only be localized with FDG-PET/CT scan.
Pulmonary diseases associated with fibrosis, including scleroderma lung disease, are characterized by the accumulation of T cells in the lungs. These cells are thought to facilitate lung fibrosis, but the exact mechanisms of their profibrotic action are not clear. Several alphaV-containing integrins, including alphaVbeta3 and alphaVbeta5, have been shown to directly activate transforming growth factor beta (TGFbeta) and promote collagen accumulation. The aim of this study was to investigate whether pulmonary T cells express profibrotic integrins and regulate collagen accumulation.
Expression of integrins was assessed by immunohistochemical analysis of lung tissue, by flow cytometry using bronchoalveolar lavage fluid from patients with systemic sclerosis (SSc), and in a CCL18 overexpression animal model of pulmonary T cell infiltration. Experiments in cell cultures were performed to determine whether integrin-expressing T cells are profibrotic in cocultures with pulmonary fibroblasts and, if so, through what possible mechanism.
Lymphocytes and integrin-positive cells were present in the lungs, and pulmonary T cells expressed integrins alphaVbeta3 and alphaVbeta5 in patients with SSc and in the animal model. Systemic administration of neutralizing anti-integrin alphaV antibody or a genetic deficiency of integrin beta3 in the CCL18 overexpression model significantly attenuated CCL18-driven pulmonary lymphocytic infiltration and collagen accumulation. Jurkat T cells overexpressing integrin alphaVbeta3 or integrin alphaVbeta5 in cocultures with primary pulmonary fibroblasts stimulated collagen accumulation and Smad2 nuclear translocation. Neutralizing anti-TGFbeta antibody attenuated the profibrotic effect of integrin-expressing T cells.
Pulmonary infiltrating T lymphocytes may express integrins alphaVbeta3 and alphaVbeta5 that are necessary for lymphocytic infiltration and T cell-associated TGFbeta activation and collagen accumulation.
The purpose of this study was to evaluate interstitial alterations in myocardial remodeling using a radiolabeled Cy5.5-RGD imaging peptide (CRIP) that targets myofibroblasts.
Collagen deposition and interstitial fibrosis contribute to cardiac remodeling and heart failure after myocardial infarction (MI). Evaluation of myofibroblastic proliferation should provide indirect evidence of the extent of fibrosis.
Of 46 Swiss-Webster mice, MI was induced in 41 by coronary artery occlusion, and 5 were unmanipulated. Of the 41 mice, 6, 6, and 5 received intravenous technetium-99m labeled CRIP for micro-single-photon emission computed tomography imaging 2, 4, and 12 weeks after MI, respectively; 8 received captopril or captopril with losartan up to 4 weeks after MI. Scrambled CRIP was used 4 weeks after MI in 6 mice; the remaining 10 of 46 mice received unradiolabeled CRIP for histologic characterization.
Maximum CRIP uptake was observed in the infarct area; quantitative uptake (percent injected dose/g) was highest at 2 weeks (2.75 +/- 0.46%), followed by 4 (2.26 +/- 0.09%) and 12 (1.74 +/- 0.24%) weeks compared with that in unmanipulated mice (0.59 +/- 0.19%). Uptake was higher at 12 weeks in the remote areas. CRIP uptake was histologically traced to myofibroblasts. Captopril alone (1.78 +/- 0.31%) and with losartan (1.13 +/- 0.28%) significantly reduced tracer uptake; scrambled CRIP uptake in infarct area (0.74 +/- 0.17%) was similar to CRIP uptake in normal myocardium.
Radiolabeled CRIP allows for noninvasive visualization of interstitial alterations during cardiac remodeling, and is responsive to antiangiotensin treatment. If proven clinically feasible, such a strategy would help identify post-MI patients likely to develop heart failure.
During normal tissue remodeling, macrophages remove unwanted cells, including those that have undergone programmed cell death, or apoptosis. This widespread process extends to the deletion of thymocytes (negative selection), in which cells expressing inappropriate Ag receptors undergo apoptosis, and are phagocytosed by thymic macrophages. Although phagocytosis of effete leukocytes by macrophages has been known since the time of Metchnikoff, only recently has it been recognized that apoptosis leads to surface changes that allow recognition and removal of these cells before they are lysed. Our data suggest that macrophages specifically recognize phosphatidylserine that is exposed on the surface of lymphocytes during the development of apoptosis. Macrophage phagocytosis of apoptotic lymphocytes was inhibited, in a dose-dependent manner, by liposomes containing phosphatidyl-L-serine, but not by liposomes containing other anionic phospholipids, including phosphatidyl-D-serine. Phagocytosis of apoptotic lymphocytes was also inhibited by the L isoforms of compounds structurally related to phosphatidylserine, including glycerophosphorylserine and phosphoserine. The membranes of apoptotic lymphocytes bound increased amounts of merocyanine 540 dye relative to those of normal cells, indicating that their membrane lipids were more loosely packed, consistent with a loss of membrane phospholipid asymmetry. Apoptotic lymphocytes were shown to express phosphatidylserine (PS) externally, because PS on their surfaces was accessible to derivatization by fluorescamine, and because apoptotic cells expressed procoagulant activity. These observations suggest that apoptotic lymphocytes lose membrane phospholipid asymmetry and expose phosphatidylserine on the outer leaflet of the plasma membrane. Macrophages then phagocytose apoptotic lymphocytes after specific recognition of the exposed PS.