Josef Machac

Atherosclerosis Inflammation Imaging with 18F-FDG PET: Carotid, Iliac, and Femoral Uptake Reproducibility, Quantification Methods, and Recommendations

Atherosclerosis imaging with 18F-FDG PET is useful for tracking inflammation within plaque and monitoring the response to drug therapy. Short-term reproducibility of this technique in peripheral artery disease has not been assessed, and the optimal method of 18F-FDG quantification is still debated. We imaged 20 patients with vascular disease using 18F-FDG PET twice, 14 d apart, and used these data to assess reproducibility measures and compare 2 methods of 18F-FDG uptake measurement. We also reviewed the literature on quantification methods to determine the optimal measures of arterial 18F-FDG uptake for future studies. Methods: Twenty patients with vascular disease underwent PET/CT of the iliac, femoral, and carotid arteries 90 min after 18F-FDG administration. In 19 patients, repeat testing was performed at 2 wk. Coregistration and attenuation correction were performed with CT. Vessel 18F-FDG uptake was measured as both the mean and maximum blood-normalized standardized uptake value (SUV), known as the target-to-background ratio (TBR). We assessed interscan, interobserver, and intraobserver agreement. Results: Nineteen patients completed both imaging sessions. The carotid and peripheral arteries all have excellent short-term reproducibility of the 18F-FDG signal, with intraclass correlation coefficients all greater than 0.8 for all measures of reproducibility. Both mean and maximum TBR measurements for quantifying 18F-FDG uptake are equally reproducible. 18F-FDG uptake was significantly higher in the carotid arteries than in both iliac and femoral vessels (P < 0.001 for both). Conclusion: We found that both mean and maximum TBR in the carotid, iliac, and femoral arteries were highly reproducible. We suggest the mean TBR be used for tracking systemic arterial therapies, whereas the maximum TBR is optimal for detecting and monitoring local, plaque-based therapy.

Cardiac Involvement in Patients with Sarcoidosis: Diagnostic and Prognostic Value of Outpatient Testing

BACKGROUND Cardiac sarcoidosis (CS) causes substantial morbidity and sudden death. Early diagnosis and risk stratification are warranted. METHODS Ambulatory patients with sarcoidosis were interviewed to determine whether they experienced palpitations, syncope, or presyncope, and were evaluated with ECG, Holter monitoring, and echocardiography (transthoracic echocardiogram [TTE]). Those with symptoms or abnormal results were studied with cardiac MRI (CMRI) or positron emission tomography (PET) scanning. The diagnosis of CS was based on abnormalities detected by these imaging studies. Patients with CS were referred for risk stratification by electrophysiology study (EPS). RESULTS Among the 62 patients evaluated, the prevalence of CS was 39%. Patients with CS had more cardiac symptoms than those without CS (46% vs 5%, respectively; p < 0.001), and were more likely to have abnormal Holter monitoring findings (50% vs 3%, respectively; p < 0.001) and TTE findings (25% vs 5%, respectively; p = 0.02). The degree of pulmonary impairment did not predict CS. Two of the 17 patients who underwent EPS had abnormal test findings and received implantable cardioverter-defibrillators. No patients died, had ventricular arrhythmias that triggered defibrillator therapy, or had heart failure develop during almost 2 years of follow-up. This diagnostic approach was more sensitive than the established criteria for identifying CS. CONCLUSION CS is common among patients with sarcoidosis. A structured clinical assessment incorporating advanced cardiac imaging with PET scanning or CMRI is more sensitive than the established criteria for the identification of CS. Sarcoidal lesions seen on CMRI or PET scanning do not predict arrhythmias in ambulatory patients with preserved cardiac function, who appear to be at low risk for short-term mortality.

Imaging Atherosclerotic Plaque Inflammation by Fluorodeoxyglucose With Positron Emission Tomography : Ready for Prime Time?

Inflammation is a determinant of atherosclerotic plaque rupture, the event leading to most myocardial infarctions and strokes. Although conventional imaging techniques identify the site and severity of luminal stenosis, the inflammatory status of the plaque is not addressed. Positron emission tomography imaging of atherosclerosis using the metabolic marker fluorodeoxyglucose allows quantification of arterial inflammation across multiple vessels. This review sets out the background and current and potential future applications of this emerging biomarker of cardiovascular risk, along with its limitations.

Relationships among regional arterial inflammation, calcification, risk factors, and biomarkers: a prospective fluorodeoxyglucose positron-emission tomography/computed tomography imaging study.

Background—Fluorodeoxyglucose positron-emission tomography (FDG PET) imaging of atherosclerosis has been used to quantify plaque inflammation and to measure the effect of plaque-stabilizing drugs. We explored how atherosclerotic plaque inflammation varies across arterial territories and how it relates to arterial calcification. We also tested the hypotheses that the degree of local arterial inflammation measured by PET is correlated with the extent of systemic inflammation and presence of risk factors for vascular disease. Methods and Results—Forty-one subjects underwent vascular PET/computed tomography imaging with FDG. All had either vascular disease or multiple risk factors. Forty subjects underwent carotid imaging, 27 subjects underwent aortic, 24 subjects iliac, and 13 subjects femoral imaging. Thirty-three subjects had a panel of biomarkers analyzed. We found strong associations between FDG uptake in neighboring arteries (left versus right carotid, r=0.91, P<0.001; ascending aorta versus aortic arch, r=0.88, P<0.001). Calcification and inflammation rarely overlapped within arteries (carotid artery FDG uptake versus calcium score, r=−0.42, P=0.03). Carotid artery FDG uptake was greater in those with a history of coronary artery disease (target-to-background ratio, 1.83 versus 1.61, P<0.01) and in males versus females (target-to-background ratio, 1.83 versus 1.63, P<0.05). Similar findings were also noted in the aorta and iliac arteries. Subjects with the highest levels of FDG uptake also had the greatest concentrations of inflammatory biomarkers (descending aorta target-to-background ratio versus matrix metalloproteinase 3, r=0.53, P=0.01; carotid target-to-background ratio versus matrix metalloproteinase 9, r=0.50, P=0.01). Nonsignificant positive trends were seen between FDG uptake and levels of interleukin-18, fibrinogen, and C-reactive protein. Finally, we found that the atheroprotective biomarker adiponectin was negatively correlated with the degree of arterial inflammation in the descending aorta (r=−0.49, P=0.03). Conclusions—This study shows that FDG PET imaging can increase our knowledge of how atherosclerotic plaque inflammation relates to calcification, serum biomarkers, and vascular risk factors. Plaque inflammation and calcification rarely overlap, supporting the theory that calcification represents a late, burnt-out stage of atherosclerosis. Inflammation in one arterial territory is associated with inflammation elsewhere, and the degree of local arterial inflammation is reflected in the blood levels of several circulating biomarkers. We suggest that FDG PET imaging could be used as a surrogate marker of both atherosclerotic disease activity and drug effectiveness. Prospective, event-driven studies are now underway to determine the role of this technique in clinical risk prediction.Background— Fluorodeoxyglucose positron-emission tomography (FDG PET) imaging of atherosclerosis has been used to quantify plaque inflammation and to measure the effect of plaque-stabilizing drugs. We explored how atherosclerotic plaque inflammation varies across arterial territories and how it relates to arterial calcification. We also tested the hypotheses that the degree of local arterial inflammation measured by PET is correlated with the extent of systemic inflammation and presence of risk factors for vascular disease. Methods and Results— Forty-one subjects underwent vascular PET/computed tomography imaging with FDG. All had either vascular disease or multiple risk factors. Forty subjects underwent carotid imaging, 27 subjects underwent aortic, 24 subjects iliac, and 13 subjects femoral imaging. Thirty-three subjects had a panel of biomarkers analyzed. We found strong associations between FDG uptake in neighboring arteries (left versus right carotid, r =0.91, P <0.001; ascending aorta versus aortic arch, r =0.88, P <0.001). Calcification and inflammation rarely overlapped within arteries (carotid artery FDG uptake versus calcium score, r =−0.42, P =0.03). Carotid artery FDG uptake was greater in those with a history of coronary artery disease (target-to-background ratio, 1.83 versus 1.61, P <0.01) and in males versus females (target-to-background ratio, 1.83 versus 1.63, P <0.05). Similar findings were also noted in the aorta and iliac arteries. Subjects with the highest levels of FDG uptake also had the greatest concentrations of inflammatory biomarkers (descending aorta target-to-background ratio versus matrix metalloproteinase 3, r =0.53, P =0.01; carotid target-to-background ratio versus matrix metalloproteinase 9, r =0.50, P =0.01). Nonsignificant positive trends were seen between FDG uptake and levels of interleukin-18, fibrinogen, and C-reactive protein. Finally, we found that the atheroprotective biomarker adiponectin was negatively correlated with the degree of arterial inflammation in the descending aorta ( r =−0.49, P =0.03). Conclusions— This study shows that FDG PET imaging can increase our knowledge of how atherosclerotic plaque inflammation relates to calcification, serum biomarkers, and vascular risk factors. Plaque inflammation and calcification rarely overlap, supporting the theory that calcification represents a late, burnt-out stage of atherosclerosis. Inflammation in one arterial territory is associated with inflammation elsewhere, and the degree of local arterial inflammation is reflected in the blood levels of several circulating biomarkers. We suggest that FDG PET imaging could be used as a surrogate marker of both atherosclerotic disease activity and drug effectiveness. Prospective, event-driven studies are now underway to determine the role of this technique in clinical risk prediction. Received August 3, 2008; accepted December 23, 2008. # CLINICAL PERSPECTIVE {#article-title-2}Background —Fluorodeoxyglucose positron emission tomography (FDG PET) imaging of atherosclerosis has been used to quantify plaque inflammation and to measure the effect of plaque stabilizing drugs. Here we explore how atherosclerotic plaque inflammation varies across arterial territories and how it relates to arterial calcification. We also test the hypotheses that the degree of local arterial inflammation measured by PET is correlated with the extent of systemic inflammation and presence of risk factors for vascular disease. Methods and Results —Forty-one subjects underwent vascular PET/CT imaging with FDG. All had either vascular disease or multiple risk factors for it. Forty subjects underwent carotid imaging, twenty-seven underwent aortic, twenty-four iliac and thirteen femoral imaging. Thirty-three subjects had a panel of biomarkers analyzed. We found strong associations between FDG uptake in neighboring arteries (left vs. right carotid r=0.91, p<0.001, ascending aorta vs. aortic arch r=0.88, p<0.001). Calcification and inflammation rarely overlapped within arteries — carotid artery FDG uptake vs. calcium score r=-0.42, p=0.03). Carotid artery FDG uptake was greater in those with a history of coronary artery disease (target to background ratio (TBR) 1.83 vs. 1.61, p<0.01), and in males vs. females (TBR 1.83 vs. 1.63, p<0.05). Similar findings were also noted in the aorta and iliac arteries. Subjects with the highest levels of FDG uptake also had the greatest concentrations of inflammatory biomarkers: descending aorta TBR vs. matrix metalloproteinase 3 (MMP 3): r=0.53, p=0.01 and carotid TBR vs. MMP 9: r=0.50, p=0.01. Non-significant positive trends were seen between FDG uptake and levels of interleukin 18, fibrinogen and C-reactive protein. Finally, we found that the atheroprotective biomarker adiponectin was negatively correlated with the degree of arterial inflammation in the descending aorta: r=-0.49, p=0.03). Conclusions —This study shows that FDG PET imaging can increase our knowledge of how atherosclerotic plaque inflammation relates to calcification, serum biomarkers and vascular risk factors. Plaque inflammation and calcification rarely overlap, supporting the theory that calcification represents a late, burnt-out stage of atherosclerosis. Inflammation in one arterial territory is associated with inflammation elsewhere, and the degree of local arterial inflammation is reflected in the blood levels of several circulating biomarkers. We suggest that FDG PET imaging could be used as a surrogate marker of both atherosclerotic disease activity and drug effectiveness. Prospective, event driven studies are now underway to determine the role of this technique in clinical risk prediction.

Patient management after noninvasive cardiac imaging: Results from SPARC (Study of myocardial perfusion and coronary anatomy imaging roles in coronary artery disease)

OBJECTIVES This study examined short-term cardiac catheterization rates and medication changes after cardiac imaging. BACKGROUND Noninvasive cardiac imaging is widely used in coronary artery disease, but its effects on subsequent patient management are unclear. METHODS We assessed the 90-day post-test rates of catheterization and medication changes in a prospective registry of 1,703 patients without a documented history of coronary artery disease and an intermediate to high likelihood of coronary artery disease undergoing cardiac single-photon emission computed tomography, positron emission tomography, or 64-slice coronary computed tomography angiography. RESULTS Baseline medication use was relatively infrequent. At 90 days, 9.6% of patients underwent catheterization. The rates of catheterization and medication changes increased in proportion to test abnormality findings. Among patients with the most severe test result findings, 38% to 61% were not referred to catheterization, 20% to 30% were not receiving aspirin, 35% to 44% were not receiving a beta-blocker, and 20% to 25% were not receiving a lipid-lowering agent at 90 days after the index test. Risk-adjusted analyses revealed that compared with stress single-photon emission computed tomography or positron emission tomography, changes in aspirin and lipid-lowering agent use was greater after computed tomography angiography, as was the 90-day catheterization referral rate in the setting of normal/nonobstructive and mildly abnormal test results. CONCLUSIONS Overall, noninvasive testing had only a modest impact on clinical management of patients referred for clinical testing. Although post-imaging use of cardiac catheterization and medical therapy increased in proportion to the degree of abnormality findings, the frequency of catheterization and medication change suggests possible undertreatment of higher risk patients. Patients were more likely to undergo cardiac catheterization after computed tomography angiography than after single-photon emission computed tomography or positron emission tomography after normal/nonobstructive and mildly abnormal study findings. (Study of Perfusion and Anatomys Role in Coronary Artery [CAD] [SPARC]; NCT00321399).

A brain imaging (single photon emission computerized tomography) study of semantic and affective processing in psychopaths

Psychopaths have been described as human predators who use charm, intimidation, and violence to control others and to satisfy their own needs. Underlying their propensity to violate social norms and expectations is a profound lack of empathy, guilt, or remorse, affective processes that have long resisted scientific investigation. Using brain imaging technology we found that psychopaths differed from nonpsychopaths in the pattern of relative cerebral blood flow during processing of emotional words. The results were consistent with the hypothesis that there are anomalies in the way psychopaths process semantic and affective information.

Detection of Neovessels in Atherosclerotic Plaques of Rabbits Using Dynamic Contrast Enhanced MRI and 18F-FDG PET

Objective—The association of inflammatory cells and neovessels in atherosclerosis is considered a histological hallmark of high-risk active lesions. Therefore, the development and validation of noninvasive imaging techniques that allow for the detection of inflammation and neoangiogenesis in atherosclerosis would be of major clinical interest. Our aim was to test 2 techniques, black blood dynamic contrast enhanced MRI (DCE-MRI) and 18-fluorine-fluorodeoxyglucose (18F-FDG) PET, to quantify inflammation expressed as plaque neovessels content in a rabbit model of atherosclerosis. Methods and Results—Atherosclerotic plaques were induced in the aorta of 10 rabbits by a combination of 2 endothelial abrasions and 4 months hyperlipidemic diet. Six rabbits underwent MRI during the injection of Gd-DTPA, whereas 4 rabbits were imaged after injection of 18F-FDG with PET. We found a positive correlation between neovessels count in atherosclerotic plaques and (1) Gd-DTPA uptake parameters evaluated by DCE-MRI (r=0.89, P=0.016) and (2) 18F-FDG uptake evaluated by PET (r=0.5, P=0.103 after clustered robust, Huber-White, standard errors analysis). Conclusion—DCE-MRI and 18F-FDG PET may allow for the evaluation of inflammation in atherosclerotic plaques of rabbits. These noninvasive imaging modalities could be proposed as clinical tools in the evaluation of lesion prognosis and monitoring of anti–angiogenic therapies.

Quantification of Inflammation Within Rabbit Atherosclerotic Plaques Using the Macrophage-Specific CT Contrast Agent N1177: A Comparison with 18F-FDG PET/CT and Histology

Macrophages play a key role in atherosclerotic plaque rupture. The iodine-based contrast agent N1177 accumulates in macrophages, allowing for their detection with CT. In this study, we tested whether the intensity of enhancement detected with CT in the aortic wall of rabbits injected with N1177 correlated with inflammatory activity evaluated with 18F-FDG PET/CT and macrophage density on histology. Methods: Atherosclerotic plaques were induced in the aorta of New Zealand White rabbits (n = 7) by a repeated balloon injury (4 wk apart) and 4 mo of hyperlipemic diet. Noninjured rabbits, fed a chow diet, were used as controls (n = 3). A CT scan of the aorta (n = 10) was acquired in each rabbit before, during, and at 2 h after intravenous injection of N1177 (250 mg of iodine/kg). One week later, the same rabbits underwent PET/CT 3 h after injection of 18F-FDG (37 MBq/kg [1 mCi/kg]). CT enhancement was calculated as the difference in aortic wall densities between images obtained before and images obtained at 2 h after injection of N1177. Mean standardized uptake values were measured on PET axial slices of the aorta in regions of interest encompassing the vessel wall. Macrophage density was measured by immunohistology (anti-RAM-11 antibody) on corresponding aortic cross-sections. Results: N1177-enhanced CT measured stronger enhancement in the aortic wall of atherosclerotic rabbits than in control rabbits (10.0 ± 5.2 vs. 2.0 ± 2.1 Hounsfield units, respectively; P < 0.05). After the injection of 18F-FDG, PET detected higher standardized uptake values in the aortic wall of atherosclerotic rabbits than in control rabbits (0.61 ± 0.12 vs. 0.21 ± 0.02; P < 0.05). The intensity of enhancement in the aortic wall measured with CT after injection of N1177 correlated with 18F-FDG uptake on PET/CT (r = 0.61, P < 0.001) and macrophage density on immunohistology (r = 0.63, P < 0.001). Conclusion: The intensity of enhancement detected with CT in the aortic wall of rabbits injected with N1177 correlates with intense uptake of 18F-FDG measured with PET and with macrophage density on histology, suggesting a role for N1177 in noninvasive identification of high-risk atherosclerotic plaques with CT.

Non-invasive imaging of atherosclerotic plaque macrophage in a rabbit model with F-18 FDG PET: a histopathological correlation

BackgroundCoronary atherosclerosis and its thrombotic complications are the major cause of mortality and morbidity throughout the industrialized world. Thrombosis on disrupted atherosclerotic plaques plays a key role in the onset of acute coronary syndromes. Macrophages density is one of the most critical compositions of plaque in both plaque vulnerability and thrombogenicity upon rupture. It has been shown that macrophages have a high uptake of 18F-FDG (FDG). We studied the correlation of FDG uptake with histopathological macrophage accumulation in atherosclerotic plaques in a rabbit model.MethodsAtherosclerosis was induced in rabbits (n = 6) by a combination of atherogenic diet and balloon denudation of the aorta. PET imaging was performed at baseline and 2 months after atherogenic diet and coregistered with magnetic resonance (MR) imaging. Normal (n = 3) rabbits served as controls. FDG uptake by the thoracic aorta was expressed as concentration (μCi/ml) and the ratio of aortic uptake-to-blood radioactivity. FDG uptake and RAM-11 antibody positive areas were analyzed in descending aorta.ResultsAtherosclerotic aortas showed significantly higher uptake of FDG than normal aortas. The correlation of aortic FDG uptake with macrophage areas assessed by histopathology was statistically significant although it was not high (r = 0.48, p < 0.0001). When uptake was expressed as the ratio of aortic uptake-to-blood activity, it correlated better (r = 0.80, p < 0.0001) with the macrophage areas, due to the correction for residual blood FDG activity.ConclusionPET FDG activity correlated with macrophage content within aortic atherosclerosis. This imaging approach might serve as a useful non-invasive imaging technique and potentially permit monitoring of relative changes in inflammation within the atherosclerotic lesion.

Atrial kinetics and left ventricular diastolic filling in the healthy elderly

A delay of left ventricular isovolumic relaxation and decrease in myocardial compliance may result in a decline of measured early filling rates in elderly subjects. Previous studies of diastolic function, however, have not excluded coronary artery disease or addressed the contribution of atrial contraction to diastole. The present study evaluated radionuclide-derived diastolic variables in 13 healthy elderly volunteers aged 75 +/- 6 years without symptoms or risk factors for coronary disease who had normal findings on the stress electrocardiogram, stress gated blood pool imaging and two-dimensional echocardiogram. Results were compared with those of a group of 10 healthy young volunteers aged 26 +/- 5 years. High count, 32 frame, double-buffered gated blood pool acquisitions were obtained at rest in the left anterior oblique view with an RR interval variation less than 5%. Left ventricular time-activity curves were analyzed and flow-volume loops for each group were constructed. In the healthy elderly: peak early diastolic filling rate is decreased, time of peak early filling and time to first third of diastolic filling are delayed, and peak late left ventricular filling rate and percent of atrial filling volume are augmented, suggesting an adaptive response of the atria to diminished left ventricular compliance.