Detection and characterization of hibernating myocardium.

Since Tennant and Wiggers observed that coronary occlusion caused a reduction in cardiac contractile function, a lot has been written about the concept of hibernating myocardium. Known as the 'smart heart', hibernating myocardium is characterized by a persistent ventricular myocardial dysfunction with preserved viability, which improves with the relief of the ischaemia; this chronic downregulation in contractile function being a protective mechanism to reduce oxygen demand and thus ensure myocyte survival. This improvement usually results in an enrichment in the quality of life as well as enhanced ventricular function. In fact, it has been observed that the cardiac event rate in patients with viable dysfunctional left ventricular segments who are medically treated, is higher than the event rate in patients with comparable viability who are revascularized. Different degrees of histological alteration have been seen in hibernating myocardium, ranging from cellular de-differentiation (fetal phenotype) to cellular degeneration. Cellular de-differentiation has been associated with repetitive stunning. On the other hand, cellular degeneration (with more extensive fibrosis) has been associated with chronic low myocardial blood flow and a longer time to recovery after revascularization. These histological patterns may suggest an evolution from cellular de-differentiation to degeneration, which ends in scar formation if no revascularization is performed. In fact, several studies have described the clinical value of identifying and revascularizing hibernating segments as early as possible, to minimize fibrosis and morbidity from adverse events. Detection of hibernating myocardium still remains an important clinical problem. Imaging modalities to assess myocardial viability must differentiate potentially functional tissue from myocardium with no potential for functional recovery. These techniques fall into three broad categories: ventricular function assessment, myocardial perfusion imaging and myocardial metabolic imaging. PET imaging with fluorine-18 fluorodeoxyglucose (18F-FDG) and 11C-acetate, single photon emission computed tomography (SPECT) with thallium and 99mTc-sestamibi, dobutamine echocardiograpy, magnetic resonance imaging (MRI) and fast computed tomography (CT) have been used for this purpose. PET imaging, in both perfusion and glucose metabolic activity, has become a standard for myocardial viability assessment, however, similar information may be available from carefully performed studies with perfusion tracers alone.

99mTc annexin V imaging of neonatal hypoxic brain injury.

BACKGROUND AND PURPOSE: Delayed cell loss in neonates after cerebral hypoxic-ischemic injury (HII) is believed to be a major cause of cerebral palsy. In this study, we used radiolabeled annexin V, a marker of delayed cell loss (apoptosis), to image neonatal rabbits suffering from HII. METHODS: Twenty-two neonatal New Zealand White rabbits had ligation of the right common carotid artery with reduction of inspired oxygen concentration to induce HII. Experimental animals (n=17) were exposed to hypoxia until an ipsilateral hemispheric decrease in the average diffusion coefficient occurred. After reversal of hypoxia and normalization of average diffusion coefficient values, experimental animals were injected with (99m)Tc annexin V. Radionuclide images were recorded 2 hours later. RESULTS: Experimental animals showed no MR evidence of blood-brain barrier breakdown or perfusion abnormalities after hypoxia. Annexin images demonstrated multifocal brain uptake in both hemispheres of experimental but not control animals. Histology of the brains from experimental animals demonstrated scattered pyknotic cortical and hippocampal neurons with cytoplasmic vacuolization of glial cells without evidence of apoptotic nuclei by terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) staining. Double staining with markers of cell type and exogenous annexin V revealed that annexin V was localized in the cytoplasm of scattered neurons and astrocytes in experimental and, less commonly, control brains in the presence of an intact blood-brain barrier. CONCLUSIONS: Apoptosis may develop after HII even in brains that appear normal on diffusion-weighted and perfusion MR. These data suggest a role of radiolabeled annexin V screening of neonates at risk for the development of cerebral palsy.

The tolerability and efficacy of the atypical neuroleptic remoxipride compared with clozapine and haloperidol in acute schizophrenia.

Remoxipride and clozapine are new neuroleptics that are thought to be superior to the substances in use by their efficacy and tolerance. At the University Clinic of Psychiatry in Düsseldorf a double-blind study with 54 patients diagnosed as schizophrenic in accordance with DSM-III was conducted to record the influence of the neuroleptics remoxipride, clozapine and haloperidol on schizophrenic psychosis. The schizophrenic symptoms were rated by the AMDP-system (Arbeitsgemeinschaft für Methodik und Dokumentation in der Psychiatrie), Brief Psychiatric Rating Scale and the Clinical Global Impression on days 0, 7, 14, 21 and 28 of treatment to evaluate the degree of change in psychopathology. The tolerance of the neuroleptic treatment was checked by the doctor's overall impression and the somatic findings of the AMDP-system. All 3 neuroleptics reduced the schizophrenic symptoms to a similar degree but showed differentiation as to their side effects.

Psychotropic effects of ritanserin, a selective S2 antagonist: an open study.

The efficacy of the S2-antagonist ritanserin has not yet been clarified satisfactorily. In an open indication finding study to generate new hypotheses concerning its possible therapeutic application carried out in the psychiatric university clinic 25 patients (10 patients with vitalized neurotic depression (ICD No. 296.1), 7 with florid depressively tinged schizophrenia (ICD No. 295.3)) were treated with an average of 15.5 mg/day of ritanserin for a period of 4 weeks. Alterations in the psychopathological findings were documented by means of the Brief Psychiatric Rating Scale (BPRS), the Hamilton Depression Scale (HAMD), the Hamilton Anxiety Scale (HAMA), and the psychopathological findings (page 4) of the AMDP system. The results suggest that ritanserin improves depressive rather than schizophrenic symptomatology. In 4 of the 7 schizophrenic patients of our study an intensification of the psychotic symptomatology could even be observed. On the basis of our open study findings ritanserin could be classified as a substance with antidepressive effects, with a low incidence of side-effects and a rapid onset of action. In placebo controlled clinical studies this indication should be examined in different patient groups.

Cognitive disturbances in neuroleptic therapy.

Eighteen patients (7 men, 11 women) from one of the centres taking part in a multicentre comparative study of remoxipride and haloperidol in the treatment of acute schizophrenia were investigated separately to study the effect of the two neuroleptic drugs on cognitive abilities. The tests of cognitive ability that were used are standard in West Germany. The results of this study indicate that there could be differences between remoxipride and haloperidol regarding their effects on cognitive abilities--the patients who had been treated for four weeks with remoxipride showed a greater "mental fitness".

Study to establish the indication for the selective S2 antagonist ritanserin.

In our open study, ritanserin was shown to be an antidepressant low in side effects with a rapid onset of action. In contrast to the results reported by Ceulemanns, patients suffering from melancholia could also be treated with ritanserin. Similar to amitriptyline, ritanserin is able to provoke psychotic symptoms in schizophrenic patients despite the absence of an anticholinergic action. Ritanserin appears to improve mood and subjective well-being of depressive schizophrenic patients as supplementary therapy to a highly potent neuroleptic. This is consistent with the experience of Gelders. The relevance of the results described is restricted by the fact that the patients received an above-average intensive medical care besides the pharmacotherapy. In addition, the expectations of the patients with regard to ritanserin were extremely high and they expected an above-average effect of the ritanserin treatment.

Comparison of 2- and 3-18F-fluoro-deoxy-D-glucose for studies of tissue metabolism.

2- and 3-18F-fluoro-deoxy-D-glucose were proposed as sugar analogs to study glucose metabolism in brain and heart tissues. To evaluate their usefulness, the in vivo behavior of 2- 28FDG and 3-18FDG was investigated in mice and rats and for 3-18FDG in dogs at various times post-injection. Positron emission tomographic (PET) imaging was performed for heart and brain of anesthetized dogs with both radiopharmaceuticals. In all species studied, a higher uptake in brain, heart and kidney was observed for 2-18FDG compared with 3-18FDG. Radioactivity also cleared blood and liver more rapidly with 2-18FDG than with 3-18FDG. Estimates of brain kinetic model parameters revealed the metabolic trapping of 2-18FDG, making this agent favorable for studies of tissue metabolism, and the relative lack of phosphorylation of 3-18FDG, which makes it a potential agent for studies of glucose transport.

Beta-methyl[1-11C]heptadecanoic acid: a new myocardial metabolic tracer for positron emission tomography.

We have tagged heptadecanoic acid with C-11 at the carboxyl group and have inserted a methyl radical in the beta position to inhibit beta oxidation of the fatty acid; we have then explored the tracer's potential as an indicator of myocardial metabolism for use with the positron tomograph. In this preliminary evaluation, biodistribution studies were made in rats and dogs, and imaging of normal and infarcted dogs was performed. At 30 min the tissue distribution studies in rats and dogs showed, respectively, 1.9% and 8.3% uptake in the heart. Sequential images of the canine heart exhibited a remarkable uptake, peaking at 16-18 min and retaining the same level of activity over the one-hour study period. Images of the heart after LAD ligation showed an area of diminished uptake corresponding to the region of infarction. Thus this agent has the basic properties required for potential use in the assessment and quantitation of free fatty-acid metabolism in the heart in a manner similar to the measurement of glucose metabolism in the brain with 2-[18F]fluoro-3-deoxy-D-glucose.

Quantification of myocardial infarction by computer-assisted positron emission tomography.

The accuracy of three-dimensional transverse section positron emission imaging for quantification of myocardial infarction size was validated and compared with the accuracy of two dimensional planar positron imaging. After induction of acute anterior myocardial infarction in anaesthetised dogs, gallium-68 albumin microspheres were injected into the left atrium. Planar and transverse section images of the thorax were obtained with a multicrystal positron camera. After staining with tetrazolium tetrachloride injected intravenously, the hearts were excised, sectioned manually, and planar imaging repeated. Each myocardial infarction was clearly delineated by transverse section imaging with high contrast ratios (mean 0.68 +/- 0.02 SEM); planar imaging identified seven of nine infarcts but with lower contrast ratios (0.24 +/- 0.04; P < 0.001). The volume of infarcted myocardium determined from transverse section images correlated well with true infarct volume (r = 0.94); whereas planar images poorly predicted infarct size (r = 0.63). Thus, computer-assisted transverse section positron imaging provides in vivo localisation of microsphere distribution for improved radioisotopic quantification of myocardial infarction.