The regulatory background of nuclear cardiology in Europe: a survey by the European Council of Nuclear Cardiology.

PURPOSE: Nuclear cardiology is a well-validated, non-invasive imaging modality that is highly cost-effective as a diagnostic and prognostic tool in the evaluation of patients with known or suspected coronary artery disease. However, the number of procedures in Europe is very far from that which would be expected on the basis of epidemiological data, particularly when comparison is made with the USA. As a preliminary step for future action aimed at improving and increasing nuclear cardiology practice in Europe, the European Council of Nuclear Cardiology performed a survey to identify the regulatory issues and the training components pertaining to the practice of nuclear cardiology. METHODS: a questionnaire was sent to 31 national nuclear medicine societies and to 40 national cardiology societies. The main areas covered by the survey were: (1) the license requirements, (2) the theoretical and practical aspects of training and (3) supervision of the stress test during a nuclear cardiology study. RESULTS: The results show that, in a setting of wide heterogeneity of national regulations, education and professional practice, nuclear medicine is a restricted and closely regulated specialty. This situation guarantees the quality and safe use of radionuclides; at the same time, however, it limits integration of nuclear medicine into the clinical arena. CONCLUSION: Cardiologists should become more involved in nuclear cardiology, to further stimulate the use of this powerful diagnostic and prognostic imaging modality.

Exercise-induced myocardial perfusion abnormalities in sickle beta-thalassemia: Tc-99m tetrofosmin gated SPECT imaging study.

PURPOSE: To determine the mechanism of myocardial ischemia in patients with sickle beta-thalassemia, we performed a scintigraphic evaluation of myocardial perfusion during exercise. SUBJECTS AND METHODS: We studied 30 patients with sickle beta-thalassemia, (mean [+/-SD] age, 37 +/- 10 years) who had no electrocardiographic (ECG), radiographic, or echo-Doppler signs of pulmonary hypertension, left ventricular hypertrophy, or impaired contractility. All patients had a hemoglobin level greater than 7 g/dL. Treadmill exercise test was performed according to the Bruce protocol. Myocardial perfusion was assessed by single-photon emission computed tomography, using Tetrofosmin Tc-99 m Myoview as radiotracer, at peak exercise and again 4 hours later. RESULTS: Eight patients (27%) developed stress-induced scintigraphic perfusion abnormalities that were reversible in all but 1 patient. Subsequent coronary angiograms were normal in all 8 patients. ST segment depression was seen during exercise in 5 of the 7 patients who had reversible perfusion defects. Except for a significantly greater white blood cell count, these 5 patients did not differ from the rest of patients by sex, age, hemoglobin level, percentage hemoglobin F, beta-thalassemia genotype, or risk factors for coronary artery disease. Three of the 5 patients with perfusion and ECG abnormalities (and another with only perfusion defects) developed a stress-induced sickling crisis. CONCLUSION: Physical stress may induce myocardial ischemia in sickle beta-thalassemia patients with normal coronary arteries and elicit painful crises. The sickling process, activated by exercise, could be the common underlying mechanism.

Mental stress-induced silent myocardial ischemia detected during ambulatory ventricular function monitoring.

BACKGROUND: Transient ischemic episodes at rest in patients with coronary artery disease have been attributed to mental stress. The means to monitor and record cardiac function changes due to mental stress is now available by utilizing the nuclear VEST. METHODS AND RESULTS: Eight, patients with angiographically documented coronary artery disease and 8 normal volunteers underwent a 4 hour session of continuous monitoring and recording of the left ventricular function, electrocardiogram, and blood pressure during exercise and mental stress. In the normal group, all subjects showed the expected normal response to exercise with an increase in ejection fraction, heart rate and blood pressure. During mental stress two subjects (25%) showed transient episodes of ejection fraction decrease that were not associated with chest pain, ST changes or significant changes in blood pressure. In the group of coronary artery disease patients, five (63%) had an ischemic response to exercise by electrocardiographic and radionuclide ventriculography criteria with evidence of chest pain in three of them. All of them revealed transient episodes of left ventricular dysfunction during mental stress. Episodes were painless, occurred at low heart rate and in most cases were accompanied by ST-segment changes. The rest of the patients with a normal response to exercise showed slight changes of the ejection fraction above the baseline. CONCLUSION: The results provide evidence that there is marked disparity in the incidence of chest pain and ST-segment changes, despite similar ischemic ejection fraction response between mental and physical stress. This is indicative of a major role of mental stress in provoking silent ischemia that potentially might provide additional clinical information compared to exercise test.

Detection of silent left ventricular dysfunction during daily activities in coronary artery disease patients by the nuclear VEST.

Myocardial ischemia during routine daily activities was studied in patients with known coronary artery disease with an ambulatory radionuclide probe and recording device (VEST) and routine rest and exercise gated blood pool imaging. Seventeen patients were monitored for 60 minutes while sitting (baseline), standing in place, walking, eating (6 patients), and urinating (4 patients). Eleven of them (64%) failed to show an augmentation of at least 5% in the LVEF on an exercise gated blood pool imaging study (Group I) and 6 (36%) showed a normal response (Group II). Three patients (18%) in Group I experienced angina. Transient left ventricular dysfunction was detected by the VEST during walking, urinating or eating in 80% of the patients in Group I and 33% in Group II (p < 0.05). During walking, mean ejection fraction slightly decreased from 45 +/- 12% to 43 +/- 13% in Group I while the ejection fraction increased from 46 +/- 8% to 51 +/- 12% in Group II (p = 0.04 for the difference in responses). Standing in place and eating did not affect the mean ejection fraction. Urination in 4 patients in Group I caused a significant drop in ejection fraction in 3 patients for a mean change from 51 +/- 9% at rest to 42 +/- 15%. By contrast, none of the patients had angina or diagnostic ECG changes during the monitoring period.(ABSTRACT TRUNCATED AT 250 WORDS)

Lymphokine production by decidual cells in allogeneic and syngeneic murine pregnancy.

The importance of T cells during pregnancy has been well established in the murine system. Depletion of CD4 and/or CD8 positive cells from the maternal circulation increases fetal abortion and inhibits placental and fetal growth. T cell mediated regulation depends on T cell-derived lymphokines such as IL-6, IL-10, GM-CSF and IL-3. Among these factors, GM-CSF and IL-3 have been shown not only to stimulate trophoblast growth but also to promote placental function. All these growth factors having a short half life in vivo must exert their effect proximally to the site of production. In the present study, biologically active GM-CSF and IL-3 produced by T cells in the maternal decidual cap, which is the closet to the fetoplacental unit maternal component, was detected. Cytoplasmic staining of total decidual cap cells in various strain combinations, using monoclonal antibodies to lymphokines, showed that the numbers of cells producing these factors vary depending on the day of pregnancy and on the strain combination used. Using indicator cell lines and neutralizing antibodies, it was seen that GM-CSF and IL-3 are produced at the eleventh day of pregnancy and secreted in both allogeneic and syngeneic pregnancies by decidual cap cells. T cell depletion experiments in vivo showed that these factors are produced by T lymphocytes. The production and secretion of biologically active CSF-1 was also evaluated in this study. Although this is not a T cell-derived lymphokine, it is shown to be produced in the uterus and affect trophoblast growth.(ABSTRACT TRUNCATED AT 250 WORDS)

Specific CSF-1 binding on murine placental trophoblasts and macrophages serves as a link to placental growth.

Previous studies have shown that the colony-stimulating factor-1 (CSF-1), stimulates the in vitro proliferation of a fetally-derived adherent, phagocytic and non-specific esterase positive placental cell population which stains positively for cytokeratin and Mac-1. Binding experiments were designed to test whether this is a direct effect of the factor on these cells. Binding/elution as well as autoradiography experiments, show that adherent placental cells specifically bind CSF-1. Based on the expression of the endothelial markers cytokeratin and vimentin three subpopulations of cells were isolated from the murine placenta: labyrinthine-derived trophoblasts (cytokeratin positive, vimentin negative), spongiotrophoblast-derived trophoblasts (cytokeratin positive, vimentin negative) and placental macrophages (cytokeratin negative, vimentin positive). 3H-Thymidine incorporation assays as well as binding experiments, showed that these cells simultaneously respond to and bind the macrophage-specific factor CSF-1. Furthermore, the results indicate that isolated trophoblasts have a low rate of growth and they are very sensitive to mitogenic stimulation, whereas placental macrophages alone have a high rate of growth and therefore are less sensitive to the mitogenic stimulus. These findings are in favour of the existence of an important cytokine regulatory network in the murine placenta, where two major cell populations may collaborate possibly via soluble factors to stimulate placental growth and thus fetal development.

Common mechanisms govern the expression of p21ras and class II MHC antigens in the murine placenta.

It has been shown that there is an inverse as well as a direct correlation between class II MHC antigen expression and the p21ras protein, depending on the cell type. By using trophoblastic cells derived from the spongiotrophoblast and labyrinthine trophoblast, the two major components of the murine placenta, we have examined the p21ras expression in these populations and how this correlates with the induction of class II MHC antigens. It has been shown that although only a small number of cells express the p21ras and class II proteins, they can be induced to express higher levels of these markers by two different treatments. Thus, gamma-interferon (gamma-IFN) induces p21ras and class II protein expression in spongiotrophoblast-derived cells, whereas 5-Azacytidine (5-AzaC) induces expression of these antigens in labyrinthine trophoblast-derived populations. Furthermore, it has been demonstrated that there is a direct correlation between the two markers, as blocking antibody to p21ras cancels the ability of gamma-IFN and 5-AzaC to induce class II antigens. As previous work from this laboratory has shown that in vivo class II induction in the placenta leads to fetal abortion, the present results suggest that both proteins are involved in a common signal transduction pathway which may lead to disruption of fetal membranes and fetal loss.

Exercise-induced myocardial dysfunction in patients with coronary artery disease with and without angina.

Left ventricular dysfunction during exercise is considered a relatively sensitive marker of ischemia in patients with coronary artery disease. The purpose of this study was to determine whether exercise-induced myocardial dysfunction was more severe in patients with angina than in patients with ischemia without angina. Seventy-seven patients with angiographically documented coronary artery disease and an abnormal left ventricular response to exercise were studied by means of gated blood pool imaging. The arteriographic and functional parameters of 24 patients with angina during exercise testing imaging. The arteriographic and functional parameters of 24 patients with angina during exercise testing were compared with those of 53 patients who were pain free at the time of the test. Both groups were similar with regard to rate of multivessel disease (50% vs 51%, p = NS) and prior myocardial infarction (46% vs 51%, p = NS), as well as age, sex, and history of angina. Mean global ejection fraction remained unchanged (but abnormal) in both groups of patients during exercise. Furthermore, evidence of new regional asynergy during exercise assessed by a five-point scoring system was found to be equally abnormal in the two groups. Results of this study suggest that the severity of exercise-induced global and regional left ventricular dysfunction is independent of the presence of absence of angina during exercise testing.

Induction of class II MHC antigen expression on the murine placenta by 5-azacytidine correlates with fetal abortion.

During the gestational cycle the placental tissue does not express class II MHC antigens and whether this phenomenon is important to fetal survival has not yet been evoked. It has been reported that class II antigen expression precedes renal and cardiac graft rejection, which may also be the case in fetal abortion. In a recent report we showed that placental cells can be induced to express class II antigens in vitro and that these cells undergo different regulatory mechanisms depending on their anatomical position in the placenta. Thus, spongiotrophoblast-derived cells express these antigens after interferon-gamma treatment, whereas labyrinthine trophoblast-derived cells are induced by 5-azacytidine. In the present study we examined the effect of 5-azacytidine on class II antigen expression in the placenta and fetal abortion in vivo. We report that 5-azacytidine, when given to pregnant females before the ectoplacental cone formation, dramatically increases fetal loss, which correlates with class II antigen expression in the labyrinthine trophoblast zone. No site effects of 5-azacytidine on placental cell proliferation, splenic T and B cell responses, or reproductive capability of treated females were observed. However, after treatment with 5-azacytidine placental cells can stimulate maternal spleen cells to proliferate in a mixed cell reaction, whereas untreated controls cannot. Furthermore, the abortive effect of 5-azacytidine can be rescued in allogeneic pregnancy by anti-paternal class II monoclonal antibody injection into the animals during the 5-azacytidine treatment. These results suggest that the maintenance of the class II antigen-negative expression on the placenta is indeed necessary to avoid maternal immune attack and ensure fetal survival.

Propafenone in the prevention of non-ventricular arrhythmias associated with the Wolff-Parkinson-White syndrome.

The antiarrhythmic effect of oral propafenone was evaluated in 10 patients with Wolff-Parkinson-White syndrome presenting with non-ventricular arrhythmias (paroxysmal supraventricular tachycardia n = 7, atrial fibrillation or flutter n = 3). The mean age was 38 +/- 13 years, the dose varied from 300 to 900 mg three times a day (mean 450 +/- 188) and the mean follow-up period was 7 +/- 3.5 months. All patients' drug responses were assessed on 12-lead electrocardiograms and 24-hour ambulatory Holter monitoring. Electrophysiologic studies were performed in cases of sustained tachycardia while echocardiography identified 2 cases with mitral valve prolapse. Four of 10 (40%) patients became asymptomatic on a starting propafenone dose of 300 mg, while 6 (60%) had recurrences necessitating an increase in dose for the complete control of the symptoms. We observed a slight slowing of the heart rate and an increase of the mean Q-T interval (P less than 0.001). Three patients reported minor side effects including nausea, dizziness and constipation that were tolerable and dosage dependent. It is concluded that propafenone is an effective and well tolerated drug for the treatment of non-ventricular arrhythmias associated with the Wolff-Parkinson-White syndrome.

Induction of class II major histocompatibility complex antigens in murine placenta by 5-azacytidine and interferon-gamma involves different cell populations.

Class II MHC antigen expression is required for recognition of an alloantigen and generation of immune response. In rodents as well as in humans primary trophoblasts do not express class II MHC antigens. In this study we focused our interest on the mechanism(s) of class II antigen suppression on murine trophoblasts. First, we examined the possibility of gene inactivation by methylation and second the possibility of lymphokine regulation of the class II genes. The first possibility was tested by treatment of placental cells with 5-azacytidine (5-AzaC), a cytidine analog which upon incorporation into the DNA inhibits further methylation, thus leading to gene activation. In order to test the second possibility we treated placental cells with interferon-gamma (IFN-gamma) or interleukin 4 (IL4) which are known to induce class II antigen expression in many systems. We showed that treatment with 5-AzaC or IFN-gamma but not IL4 significantly increased class II expression on cytokeratin-positive and vimentin-negative adherent placental cells. Following placental cell fractionation we distinguished three cell subsets with different responsiveness to 5-AzaC and IFN-gamma. The first, characterized as placental macrophages, were induced to express class II MHC antigens only after IFN-gamma treatment. The other two subsets, characterized as trophoblasts, were isolated from the labyrinthine- and spongio-trophoblast layer of the placenta and showed class II inducibility to 5-AzaC and IFN-gamma, respectively. The results show that depending on the anatomical localization of trophoblasts within the placenta, various regulatory elements control gene expression, so that the placental barrier provides fetal protection at different levels.