SPECT/CT imaging of inflammation and calcification in human carotid atherosclerosis to identify the plaque at risk of rupture.

BACKGROUND: Calcification and inflammation are atherosclerotic plaque compositional biomarkers that have both been linked to stroke risk. The aim of this study was to evaluate their co-existing prevalence in human carotid plaques with respect to plaque phenotype to determine the value of hybrid imaging for the detection of these biomarkers. METHODS: Human carotid plaque segments, obtained from endarterectomy, were incubated in [111In]In-DOTA-butylamino-NorBIRT ([111In]In-Danbirt), targeting Leukocyte Function-associated Antigen-1 (LFA-1) on leukocytes. By performing SPECT/CT, both inflammation from DANBIRT uptake and calcification from CT imaging were assessed. Plaque phenotype was classified using histology. RESULTS: On a total plaque level, comparable levels of calcification volume existed with different degrees of inflammation and vice versa. On a segment level, an inverse relationship between calcification volume and inflammation was evident in highly calcified segments, which classify as fibrocalcific, stable plaque segments. In contrast, segments with little or no calcification presented with a moderate to high degree of inflammation, often coinciding with the more dangerous fibrous cap atheroma phenotype. CONCLUSION: Calcification imaging alone can only accurately identify highly calcified, stable, fibrocalcific plaques. To identify high-risk plaques, with little or no calcification, hybrid imaging of calcification and inflammation could provide diagnostic benefit.

Perspectives on Small Animal Radionuclide Imaging; Considerations and Advances in Atherosclerosis.

This review addresses nuclear SPECT and PET imaging in small animals in relation to the atherosclerotic disease process, one of our research topics of interest. Imaging of atherosclerosis in small animal models is challenging, as it operates at the limits of current imaging possibilities regarding sensitivity, and spatial resolution. Several topics are discussed, including technical considerations that apply to image acquisition, reconstruction, and analysis. Moreover, molecules developed for or applied in these small animal nuclear imaging studies are listed, including target-directed molecules, useful for imaging organs or tissues that have elevated expression of the target compared to other tissues, and molecules that serve as substrates for metabolic processes. Differences between animal models and human pathophysiology that should be taken into account during translation from animal to patient as well as differences in tracer behavior in animal vs. man are also described. Finally, we give a future outlook on small animal radionuclide imaging in atherosclerosis, followed by recommendations. The challenges and solutions described might be applicable to other research fields of health and disease as well.

Imaging of atherosclerosis, targeting LFA-1 on inflammatory cells with 111In-DANBIRT.

BACKGROUND: 111In-DOTA-butylamino-NorBIRT (DANBIRT) is a novel radioligand which binds to Leukocyte Function-associated Antigen-1 (LFA-1), expressed on inflammatory cells. This study evaluated 111In-DANBIRT for the visualization of atherosclerotic plaque inflammation in mice. METHODS AND RESULTS: ApoE-/- mice, fed an atherogenic diet up to 20 weeks (n = 10), were imaged by SPECT/CT 3 hours post injection of 111In-DANBIRT (~ 200 pmol, ~ 40 MBq). Focal spots of 111In-DANBIRT were visible in the aortic arch of all animals, with an average Target-to-Background Ratio (TBR) of 1.7 ± 0.5. In vivo imaging results were validated by ex vivo SPECT/CT imaging, with a TBR up to 11.5 (range 2.6 to 11.5). Plaques, identified by Oil Red O lipid-staining on excised arteries, co-localized with 111In-DANBIRT uptake as determined by ex vivo autoradiography. Subsequent histological processing and in vitro autoradiography confirmed 111In-DANBIRT uptake at plaque areas containing CD68 expressing macrophages and LFA-1 expressing inflammatory cells. Ex vivo incubation of a human carotid endarterectomy specimen with 111In-DANBIRT (~ 950 nmol, ~ 190 MBq) for 2 hours showed heterogeneous plaque uptake on SPECT/CT, after which immunohistochemical analysis demonstrated co-localization of 111In-DANBIRT uptake and CD68 and LFA-1 expressing cells. CONCLUSIONS: Our results indicate the potential of radiolabeled DANBIRT as a relevant imaging radioligand for non-invasive evaluation of atherosclerotic inflammation.

Dobutamine stress MRI versus threedimensional contrast echocardiography: It's all Black and White.

Dobutamine stress magnetic resonance imaging is considered the superior stress modality to detect wall motion abnormalities. In this report we demonstrate the strengths of a newly developed stress modality: dobutamine stress contrastenhanced real-time three-dimensional echocardiography. This stress modality may become a competitor of stress magnetic resonance imaging allowing fast acquisition and an unlimited number of left ventricular cross sections. Unfortunately, at the moment adequate imaging with stress realtime three-dimensional echocardiography is only possible in a minority of cardiac patients. (Neth Heart J 2008;16:217-8.).

Three-dimensional echocardiography.

Three-dimensional (3-D) echocardiography has been an important research goal ever since the introduction of two-dimensional (2-D) echocardiography. Most approaches towards 3-D echocardiography were off-line and based on the sequential rotational scanning and acquisition of multiple cross-sectional images together with external or internal reference systems. These approaches were limited by long acquisition and analysis time in combination with poor image quality. Recently, improvements in the matrix array technology have significantly increased spatial and temporal resolution of second-generation real-time 3-D transducers. Clinical use of modern 3-D echocardiography is boosted by the marked reduction in acquisition time and the unique possibility of on-line rendering on the ultrasound system. The integration and future quantification of new parameters together with on-line review allows new insights into cardiac function, morphology and synchrony that offer great potentials in the evaluation of right and left global and regional function, diagnosis of small areas of ischemia, congenital and valvular heart disease and effects of biventricular pacing in dilated heart asynchrony. This report will review current and future applications of 3-D data acquisition, emphasizing the real-time methods and clinical applications of the new matrix array transducer.

Long term outcome in patients with silent versus symptomatic ischaemia during dobutamine stress echocardiography.

OBJECTIVES: To compare the long term prognosis of patients having silent versus symptomatic ischaemia during dobutamine stress echocardiography (DSE). DESIGN: Observational study. SETTING: Tertiary referral centre. PATIENTS: 931 patients who experienced stress induced myocardial ischaemia during DSE. RESULTS: Silent ischaemia was present in 643 of 931 patients (69%). The number of dysfunctional segments at rest (mean (SD) 9.6 (5.1) v 8.8 (5.0), p = 0.1) and of ischaemic segments (3.5 (2.2) v 3.8 (2.1), p = 0.2) was comparable in both groups. During a mean (SD) follow up of 5.5 (3.3) years, there were 169 (18%) cardiac deaths and 86 (9%) non-fatal infarctions. Multivariable Cox regression analysis showed age (hazard ratio (HR) 1.1, 95% confidence interval (CI) 1.02 to 1.05), previous myocardial infarction (HR 1.4, 95% CI 1.1 to 2.0), and number of ischaemic segments during the test (HR 2.0, 95% CI 1.0 to 3.7) as independent predictors of cardiac death and myocardial infarction. For every additional ischaemic segment there was a twofold increment in risk of late cardiac events. The annual cardiac death or myocardial infarction rate was 3.0% in patients with symptomatic ischaemia and 4.6% in patients with silent ischaemia (p < 0.01). Silent induced ischaemia was an independent predictor of cardiac death and myocardial infarction (HR 1.7, 95% CI 1.1 to 2.0). During follow up symptomatic patients were treated more often with cardioprotective therapy (p < 0.01) and coronary revascularisation (145 of 288 (50%) v 174 of 643 (27%), p < 0.001). CONCLUSIONS: Patients with silent ischaemia had a similar extent of myocardial ischaemia during DSE compared to patients with symptomatic ischaemia but received less cardioprotective treatment and coronary revascularisation and experienced a higher cardiac event rate.

Improvement of stress LVEF rather than rest LVEF after coronary revascularisation in patients with ischaemic cardiomyopathy and viable myocardium.

OBJECTIVE: To evaluate prospectively the response of left ventricular ejection fraction (LVEF) to high dose dobutamine infusion in patients showing substantial viability, with and without improved resting LVEF after revascularisation. METHODS: Before and 9-12 months after revascularisation, 50 patients with ischaemic cardiomyopathy (LVEF 32 (8)%) and substantial myocardial viability (> or = 4 viable segments) underwent radionuclide ventriculography and dobutamine stress echocardiography. Patients were divided into group 1, patients with, and group 2, patients without significant improvement in resting LVEF (> or = 5% by radionuclide ventriculography) after revascularisation. The response of LVEF during dobutamine stress echocardiography was compared in these two groups. RESULTS: Groups 1 and 2 were comparable in baseline characteristics, resting LVEF, and number of viable segments (mean (SD) 7 (4) v 6 (2), not significant). After revascularisation, the LVEF response during dobutamine stress echocardiography improved significantly in both groups (group 1, 34 (10)% to 56 (8)%; group 2, 32 (10)% to 46 (11)%; both p < 0.001). Interestingly, although resting LVEF did not improve in group 2, peak stress LVEF after revascularisation did (p < 0.001). Group 1 patients had, however, a greater increase in peak stress LVEF (group 1, 22 (10)%; group 2, 13 (9)%; p < 0.01). New York Heart Association and Canadian Cardiovascular Society classes decreased in both groups. CONCLUSIONS: Although patients with viable myocardium did not always have improved rest LVEF after revascularisation, peak stress LVEF improved. Assessment of improvement of resting function may not be the ideal end point to evaluate successful revascularisation.

Prognostic value of dobutamine stress echocardiography in patients with previous coronary revascularisation.

OBJECTIVE: To assess the prognostic value of dobutamine stress echocardiography (DSE) in patients with previous myocardial revascularisation. DESIGN: Prospective study. SETTING: Tertiary referral centre in Rotterdam, the Netherlands. PATIENTS: 332 consecutive patients with previous percutaneous or surgical coronary revascularisation underwent DSE. Follow up was successful for 331 (99.7%) patients. Thirty eight patients who underwent early revascularisation (

Pulsed wave tissue Doppler imaging for the quantification of contractile reserve in stunned, hibernating, and scarred myocardium.

OBJECTIVES: To assess whether quantification of myocardial systolic velocities by pulsed wave tissue Doppler imaging can differentiate between stunned, hibernating, and scarred myocardium. DESIGN: Observational study. SETTING: Tertiary referral centre. PATIENTS: 70 patients with reduced left ventricular function caused by chronic coronary artery disease. METHODS: Pulsed wave tissue Doppler imaging was done close to the mitral annulus at rest and during low dose dobutamine; systolic ejection velocity (Vs) and the difference in Vs between low dose dobutamine and the resting value (DeltaVs) were assessed using a six segment model. Assessment of perfusion (with Tc-99m-tetrofosmin SPECT) and glucose utilisation (by 18F-fluorodeoxyglucose SPECT) was used to classify dysfunctional regions (by resting cross sectional echocardiography) as stunned, hibernating, or scarred. RESULTS: 253 of 420 regions (60%) were dysfunctional. Of these, 132 (52%) were classified as stunned, 25 (10%) as hibernating, and 96 (38%) as scarred. At rest, Vs in stunned, hibernating, and scar tissue was, respectively, 6.3 (1.8), 6.6 (2.2), and 5.5 (1.5) cm/s (p = 0.001 by ANOVA). There was a gradual decline in Vs during low dose dobutamine infusion between stunned, hibernating, and scar tissue (8.3 (2.6) v 7.8 (1.5) v 6.8 (1.9) cm/s, p < 0.001 by ANOVA). DeltaVs was higher in stunned (2.1 (1.9) cm/s) than in hibernating (1.2 (1.4) cm/s, p < 0.05) or scarred regions (1.3 (1.2) cm/s, p = 0.001). CONCLUSIONS: Quantitative tissue Doppler imaging showed a gradual reduction in regional velocities between stunned, hibernating, and scarred myocardium. Dobutamine induced contractile reserve was higher in stunned regions than in hibernating and scarred myocardium, reflecting different severities of myocardial damage.

Feasibility of 3D harmonic contrast imaging.

Improved endocardial border delineation with the application of contrast agents should allow for less complex and faster tracing algorithms for left ventricular volume analysis. We developed a fast rotating phased array transducer for 3D imaging of the heart with harmonic capabilities making it suitable for contrast imaging. In this study the feasibility of 3D harmonic contrast imaging is evaluated in vitro. A commercially available tissue mimicking flow phantom was used in combination with Sonovue. Backscatter power spectra from a tissue and contrast region of interest were calculated from recorded radio frequency data. The spectra and the extracted contrast to tissue ratio from these spectra were used to optimize the excitation frequency, the pulse length and the receive filter settings of the transducer. Frequencies ranging from 1.66 to 2.35 MHz and pulse lengths of 1.5, 2 and 2.5 cycles were explored. An increase of more than 15 dB in the contrast to tissue ratio was found around the second harmonic compared with the fundamental level at an optimal excitation frequency of 1.74 MHz and a pulse length of 2.5 cycles. Using the optimal settings for 3D harmonic contrast recordings volume measurements of a left ventricular shaped agar phantom were performed. Without contrast the extracted volume data resulted in a volume error of 1.5%, with contrast an accuracy of 3.8% was achieved. The results show the feasibility of accurate volume measurements from 3D harmonic contrast images. Further investigations will include the clinical evaluation of the presented technique for improved assessment of the heart.