Daniel Fagret

Prognostic value of thallium-201 single-photon emission computed tomographic myocardial perfusion imaging according to extent of myocardial defect: Study in 1,926 patients with foilow-up at 33 months☆

OBJECTIVES This study was designed to assess the prognostic value of thallium-201 single-photon emission computed tomographic (thallium SPECT) perfusion imaging in patients evaluated for stable angina pectoris and to examine the relation, if any, between the presence and extent of myocardial defect and future fatal or nonfatal cardiovascular events (revascularization, secondary myocardial infarction). BACKGROUND Compared with planar scintigraphy, thallium SPECT enables better evaluation of the extent of myocardial perfusion defect. However, its prognostic value has not yet been studied in a large population of patients. METHODS Between 1987 and 1989 we studied 3,193 patients. After exclusion of patients with unstable angina, myocardial infarction during the previous month or earlier revascularization, 1,926 patients were followed up for 33 +/- 10 (mean +/- SD) months after stress thallium SPECT imaging (performed after exercise in 1,121 patients or during dipyridamole infusion in 805 patients). Thallium SPECT imaging of the left ventricle was divided into six segments. RESULTS After normal thallium SPECT imaging (715 patients), the annual total and cardiovascular mortality rates were, respectively, 0.42%/year and 0.10%/year and were significantly higher after abnormal thallium SPECT imaging (respectively, 2.1%, relative risk 5, p = 0.012; 1.5%, relative risk 15, p < 0.0001 [log-rank test]). There was a significant relation between the number of abnormal segments and cardiovascular mortality during follow-up (p < 0.02) or the occurrence of nonfatal events (p < 0.001). The extent of defect on the initial scan provided the best SPECT variable for long-term prognosis. Thallium SPECT imaging provided additive prognostic information compared with other clinical variables (gender, previous myocardial infarction) and exercise electrocardiogram. CONCLUSIONS In patients with stable angina, normal thallium SPECT imaging indicates a low risk patient, and the extent of myocardial defect is an important prognostic predictive factor.

Long-Term Additive Prognostic Value of Thallium-201 Myocardial Perfusion Imaging Over Clinical and Exercise Stress Test in Low to Intermediate Risk Patients Study in 1137 Patients With 6-Year Follow-Up

BACKGROUND The exercise treadmill test (ETT) and Tl201 single proton emission computed tomography (SPECT) are of short- to medium-term prognostic value in coronary heart disease. We assessed the long-term prognostic value of these tests in a large population of patients with low- to intermediate risk of cardiac events. METHODS AND RESULTS One thousand one hundred thirty-seven patients (857 men, age 55+/-9 years) referred for typical (62.1%) or atypical (22.4%) chest pain, or suspected silent ischemia (15.5%), were followed up for 72+/-18 months. Overall mortality was higher after strongly positive (ST depression >2 mm, or >1 mm for a workload </=75 W) (2. 36%/y) or nondiagnostic ETT (1.63%/y) than after normal (0.85%/y) or positive ETT (1.37%/y) (P=0.002), and after abnormal SPECT than after normal SPECT (1.60%/y versus 0.68%/y, P=0.001). The major cardiac event rate (cardiac death or myocardial infarction [MI]) was 0.88%, 1.59%, 2.10%, and 2.13%/y after negative, positive, strongly positive, and nondiagnostic ETT, respectively (P=0.003), and 0.56%, 1.43%, and 2.05%/y in patients with 0, 1 to 2, and >/=3 abnormal segments on SPECT, respectively (P<0.002). An abnormal SPECT was predictive of MI (P<0.001), whereas ETT was not. In multivariate analysis, SPECT was of incremental prognostic value over clinical and ETT data for predicting overall mortality and major cardiac events. CONCLUSIONS The incremental predictive value of SPECT is maintained over 6 years and is particularly relevant after positive, strongly positive, and nondiagnostic ETT.

Additive value of thallium single-photon emission computed tomography myocardial imaging for prediction of perioperative events in clinically selected high cardiac risk patients having abdominal aortic surgery

The present study was designed to prospectively evaluate whether reinjection thallium-201 single-photon emission computed tomography (SPECT) has a significant additive predictive value for occurrence of perioperative cardiac events in clinically selected patients at high cardiac risk undergoing abdominal aortic surgery. Of a group of 517 consecutive patients referred, 134 had > or = 2 of the following clinical or electrocardiographic cardiac risk variables: age > 70 years; history of myocardial infarction, angina, or congestive heart failure; diabetes mellitus; hypertension with severe left ventricular hypertrophy; and Q waves or ischemic ST-segment abnormalities on electrocardiogram at rest. Operation was performed after thallium SPECT study. Twelve patients (9%) had major perioperative events (cardiac death or nonfatal myocardial infarction) and 18 patients had other cardiac events (unstable angina, congestive heart failure, or severe ventricular tachyarrhythmia). Variables correlated with the occurrence of major events were history of myocardial infarction (p < 0.05) and the presence (p < 0.001) and number of segments with thallium reversible defects (p < 0.001). In multivariate analysis, history of myocardial infarction (p < 0.05) and the number of segments with reversible thallium defects (p < 0.001) were independent predictors. When all the cardiac events were taken into consideration, all the previous variables, as well as Q waves and ischemic ST abnormalities on the electrocardiogram, showed significant predictive value in both univariate and multivariate analyses. Furthermore, thallium SPECT imaging has an additive predictive value for major cardiac events over clinical and electrocardiographic risk factors. When performed on clinically selected patients at high cardiac risk undergoing abdominal aortic surgery, thallium SPECT demonstrates significant prognostic value for cardiac events over that provided by clinical variables alone.

Nanobodies Targeting Mouse/Human VCAM1 for the Nuclear Imaging of Atherosclerotic Lesions

Rationale: A noninvasive tool allowing the detection of vulnerable atherosclerotic plaques is highly needed. By combining nanomolar affinities and fast blood clearance, nanobodies represent potential radiotracers for cardiovascular molecular imaging. Vascular cell adhesion molecule-1 (VCAM1) constitutes a relevant target for molecular imaging of atherosclerotic lesions. Objective: We aimed to generate, radiolabel, and evaluate anti-VCAM1 nanobodies for noninvasive detection of atherosclerotic lesions. Methods and Results: Ten anti-VCAM1 nanobodies were generated, radiolabeled with technetium-99m, and screened in vitro on mouse and human recombinant VCAM1 proteins and endothelial cells and in vivo in apolipoprotein E–deficient (ApoE−/−) mice. A nontargeting control nanobody was used in all experiments to demonstrate specificity. All nanobodies displayed nanomolar affinities for murine VCAM1. Flow cytometry analyses using human human umbilical vein endothelial cells indicated murine and human VCAM1 cross-reactivity for 6 of 10 nanobodies. The lead compound cAbVCAM1-5 was cross-reactive for human VCAM1 and exhibited high lesion-to-control (4.95±0.85), lesion-to-heart (8.30±1.11), and lesion-to-blood ratios (4.32±0.48) (P<0.05 versus control C57Bl/6J mice). Aortic arch atherosclerotic lesions of ApoE−/− mice were successfully identified by single-photon emission computed tomography imaging. 99mTc-cAbVCAM1-5 binding specificity was demonstrated by in vivo competition experiments. Autoradiography and immunohistochemistry further confirmed cAbVCAM1-5 uptake in VCAM1-positive lesions. Conclusions: The 99mTc-labeled, anti-VCAM1 nanobody cAbVCAM1-5 allowed noninvasive detection of VCAM1 expression and displayed mouse and human cross-reactivity. Therefore, this study demonstrates the potential of nanobodies as a new class of radiotracers for cardiovascular applications. The nanobody technology might evolve into an important research tool for targeted imaging of atherosclerotic lesions and has the potential for fast clinical translation.

Nitroimidazoles and hypoxia imaging: synthesis of three technetium-99m complexes bearing a nitroimidazole group: biological results

Several Tc-99m complexes were synthesized, substituted with a nitroimidazole group, in order to visualize hypoxic tissues. The complexes were tested on rats (isolated hearts) and showed no significant uptake under hypoxic conditions.

[123I]-6-deoxy-6-iodo-d-glucose (6DIG): A potential tracer of glucose transport

A glucose analogue labelled with iodine-123 in position 6 has been synthesized: [123I]-6-deoxy-6-iodo-D-glucose (6DIG). The aim of this study was to examine its biological behaviour in order to assess whether it could be used to evaluate glucose transport with SPECT. To establish whether 6DIG enters the cells using the glucose transporter, four biological models have been used: human erythrocytes in suspension, neonatal rat cardiomyocytes in culture, isolated perfused rat hearts, and biodistribution in mice. 6DIG competed with D-glucose to enter the cells and its entry was increased by insulin and inhibited in the presence of cytochalasin B. The biological behaviour of 6DIG was similar to that of 3-O-methyl-D-glucose. 6DIG is a tracer of glucose transport which is very promising for clinical studies.

Pre-clinical and clinical evaluation of nuclear tracers for the molecular imaging of vulnerable atherosclerosis: an overview

Cardiovascular diseases (CVD) are the leading cause of mortality worldwide. Despite major advances in the treatment of CVD, a high proportion of CVD victims die suddenly while being apparently healthy, the great majority of these accidents being due to the rupture or erosion of a vulnerable coronary atherosclerotic plaque. A non-invasive imaging methodology allowing the early detection of vulnerable atherosclerotic plaques in selected individuals prior to the occurrence of any symptom would therefore be of great public health benefit. Nuclear imaging could allow the identification of vulnerable patients by non-invasive in vivo scintigraphic imaging following administration of a radiolabeled tracer. The purpose of this review is to provide an overview of radiotracers that have been recently evaluated for the detection of vulnerable plaques together with the biological rationale that initiated their development. Radiotracers targeted at the inflammatory process seem particularly relevant and promising. Recently, macrophage targeting allowed the experimental in vivo detection of atherosclerosis using either SPECT or PET. A few tracers have also been evaluated clinically. Targeting of apoptosis and macrophage metabolism both allowed the imaging of vulnerable plaques in carotid vessels of patients. However, nuclear imaging of vulnerable plaques at the level of coronary arteries remains challenging, mostly because of their small size and their vicinity with unbound circulating tracer. The experimental and pilot clinical studies reviewed in the present paper represent a fundamental step prior to the evaluation of the efficacy of any selected tracer for the early, non-invasive detection of vulnerable patients.

Assessment of Myocardial Viability in Patients With Previous Myocardial Infarction by Using Single-Photon Emission Computed Tomography With a New Metabolic Tracer: [123I]-16-Iodo-3-Methylhexadecanoic Acid (MIHA): Comparison With the Rest-Reinjection Thallium-201 Technique☆

OBJECTIVES We compared the ability of rest single-photon emission computed tomography (SPECT) with [123I]-16-iodo-3-methylhexadecanoic acid (MIHA) and the thallium-201 (Tl-201) rest-reinjection technique to detect myocardial viability after infarction. BACKGROUND After myocardial infarction, MIHA frequently shows increased uptake in the areas with exercise Tl-201 defects (mismatch), even in patients with an irreversible Tl-201 reinjection defect. Whether such increased uptake is indicative of ischemic but viable myocardium is not known. METHODS We studied 38 patients who 1) underwent exercise SPECT Tl-201 with rest-reinjection and rest SPECT with MIHA before undergoing percutaneous transluminal coronary angioplasty (PTCA) of an infarct-related coronary artery, and 2) were found to have successful revascularization at follow-up angiography. The relation between SPECT results before PTCA and subsequent improvement in left ventricular wall motion was assessed. RESULTS A mismatch was evident before PTCA in 51 of 76 infarct-related segments and correlated with subsequent improvement in wall motion (overall accuracy 71%), even for the 27 segments whose exercise defects remained irreversible after Tl-201 reinjection (overall accuracy 81%). The finding of a mismatch clearly enhanced the results provided by the finding of > or = 50% Tl-201 uptake as determined at redistribution (p < 0.05), but not as determined at reinjection, although there was a trend toward a better specificity for the findings of a mismatch. CONCLUSIONS MIHA is an efficient marker of viability inside exercise-underperfused areas after infarction, even in patients with irreversible Tl-201 reinjection defects. Assessment by conventional SPECT of a mismatch between results obtained with a metabolic tracer (MIHA) and a flow tracer analyzed at exercise (Tl-201) as a marker of myocardial viability is a promising area of research.

Kinetics of iodomethylated hexadecanoic acid metabolism in the rat myocardium: influence of the number and the position of methyl radicals

The methyl-branched fatty acids, if radioiodine labelled in alpha position, are potentially adapted to a selective study of FA myocardial uptake. To determine the position and the number of methyl radicals that are necessary to obtain a maximal uptake and a minimal degradation, we measured time-activity evolution of isolated and perfused rat hearts after an injection of iodinated fatty acids which are mono- or dimethylated in alpha or beta position. Except for dimethyl fatty acid, the uptake is similar for all fatty acids studied to that of the straight chain analogue; beta mono- or dimethyl fatty acids seem best adapted to a study of the uptake because alpha monomethyl fatty acids undergo a metabolic degradation and alpha mono- and dimethyl fatty acids induce ventricular fibrillations.

Effects of amlodipine on baroreflex and sympathetic nervous system activity in mild-to-moderate hypertension*

To investigate the effect of amlodipine on baroreflex sensitivity and sympathetic system activity, 36 patients with essential hypertension were randomized to once-daily, double-blind treatment with amlodipine 5 mg or placebo 5 mg for 60 days. Measurements with a Finapres device allowed calculation of baroreflex sensitivity and blood pressure (BP) variability. Adrenergic activity was assessed via measurements of lymphocyte beta2-adrenoceptors and plasma catecholamine concentrations. Compared with placebo, amlodipine significantly decreased BP, but did not significantly alter baroreflex sensitivity. Spectral analysis of Finapres data showed that, compared with placebo, amlodipine decreased the variability of systolic blood pressure, diastolic blood pressure, and RR interval in the low frequency band. There were no simultaneous changes in adrenergic function, however, suggesting that these effects of amlodipine were not mediated via sympathetic nervous system activation.