Intraplaque Hemorrhage and the Plaque Surface in Carotid Atherosclerosis: The Plaque At RISK Study (PARISK).

BACKGROUND AND PURPOSE: An important characteristic of vulnerable plaque, intraplaque hemorrhage, may predict plaque rupture. Plaque rupture can be visible on noninvasive imaging as a disruption of the plaque surface. We investigated the association between intraplaque hemorrhage and disruption of the plaque surface. MATERIALS AND METHODS: We selected the first 100 patients of the Plaque At RISK study, an ongoing prospective noninvasive plaque imaging study in patients with mild-to-moderate atherosclerotic lesions in the carotid artery. In carotid artery plaques, disruption of the plaque surface (defined as ulcerated plaques and/or fissured fibrous cap) and intraplaque hemorrhage were assessed by using MDCTA and 3T MR imaging, respectively. We used a χ(2) test and multivariable logistic regression to assess the association between intraplaque hemorrhage and disrupted plaque surface. RESULTS: One hundred forty-nine carotid arteries in 78 patients could be used for the current analyses. Intraplaque hemorrhage and plaque ulcerations were more prevalent in symptomatic compared with contralateral vessels (hemorrhage, 38% versus 11%; P < .001; and ulcerations, 27% versus 7%; P = .001). Fissured fibrous cap was more prevalent in symptomatic compared with contralateral vessels (13% versus 4%; P = .06). After adjustment for age, sex, diabetes mellitus, and degree of stenosis, intraplaque hemorrhage was associated with disrupted plaque surface (OR, 3.13; 95% CI, 1.25-7.84) in all vessels. CONCLUSIONS: Intraplaque hemorrhage is associated with disruption of the plaque surface in patients with a carotid artery stenosis of <70%. Serial studies are needed to investigate whether intraplaque hemorrhage indeed increases the risk of plaque rupture and subsequent ischemic stroke during follow-up.

Plaque At RISK (PARISK): prospective multicenter study to improve diagnosis of high-risk carotid plaques.

BACKGROUND: Patients with symptomatic carotid artery stenosis are at high risk for recurrent stroke. To date, the decision to perform carotid endarterectomy in patients with a recent cerebrovascular event is mainly based on degree of stenosis of the ipsilateral carotid artery. However, additional atherosclerotic plaque characteristics might be better predictors of stroke, allowing for more precise selection of patients for carotid endarterectomy. AIMS AND HYPOTHESIS: We investigate the hypothesis that the assessment of carotid plaque characteristics with magnetic resonance imaging, multidetector-row computed tomography angiography, ultrasonography, and transcranial Doppler, either alone or in combination, may improve identification of a subgroup of patients with < 70% carotid artery stenosis with an increased risk of recurrent stroke. METHODS: The Plaque At RISK (PARISK) study is a prospective multicenter cohort study of patients with recent (<3 months) neurological symptoms due to ischemia in the territory of the carotid artery and < 70% ipsilateral carotid artery stenosis who are not scheduled for carotid endarterectomy or stenting. At baseline, 300 patients will undergo magnetic resonance imaging, multidetector-row computed tomography angiography, and ultrasonography examination of the carotid arteries. In addition, magnetic resonance imaging of the brain, ambulatory transcranial Doppler recording of the middle cerebral artery and blood withdrawal will be performed. After two-years, imaging will be repeated in 150 patients. All patients undergo a follow-up brain magnetic resonance imaging, and there will be regular clinical follow-up until the end of the study. STUDY OUTCOMES: The combined primary end-point contains ipsilateral recurrent ischemic stroke or transient ischemic attack or new ipsilateral ischemic brain lesions on follow-up brain magnetic resonance imaging.

The effect of single engine fixed wing air transport on rate-responsive pacemakers.

BACKGROUND: Insufficient information exists about the safety of patients with accelerometer-based rate-responsive pacemakers in air transport by general aviation aircraft. METHODS: The response in pacing rate of two types of accelerometer-based rate-responsive pacemakers with data logging capabilities was studied during test flights with single engine fixed wing aircraft. Results were compared with the rate-response of these pacemakers during transportation by car and were also interpreted in respect to physiological heart rate response of aircrew during flights in single engine fixed wing aircraft. In addition, a continuous accelerometer readout was recorded during a turbulent phase of flight. This recording was used for a pacemaker-simulator experiment with maximal sensitive motion-sensor settings. RESULTS: Only a minor increase in pacing rate due to aircraft motion could be demonstrated during all phases of flight at all altitudes with the pacemakers programmed in the normal mode. This increase was of the same magnitude as induced during transport by car and would be of negligible influence on the performance of the individual pacemaker patient equipped with such a pacemaker. Moreover, simultaneous Holter monitoring of the pilots during these flights showed a similar rate-response in natural heart rate compared with the increase in pacing rate induced by aircraft motion in accelerometer-based rate-responsive pacemakers. No sensor-mediated pacemaker tachycardia was seen during any of these recordings. However, a 15% increase in pacing rate was induced by severe air turbulence. Programming the maximal sensitivity of the motion sensor into the pacemaker could, on the other hand, induce a significant increase in pacing rate as was demonstrated by the simulation experiments. CONCLUSION: These results seem to rule out potentially dangerous or adverse effects from motional or vibrational influences during transport in single engine fixed wing aircraft on accelerometer-based rate-responsive pacemakers with normal activity sensor settings.

Characterization of alpha-MSH-like immunoreactivity in human plasma.

We report new information on the presence of alpha-melanotropin(alpha-MSH)-like immunoreactivity in the peripheral circulation of the adult human. Pooled blood from 20 patients with non-endocrine diseases was subjected to a Sep-pak pre-purification followed by a high pressure liquid chromatographic (HPLC) fractionation. The eluate from the HPLC column was analyzed by a radioimmunoassay (RIA) specific for the C-terminal part of the alpha-MSH molecule. From this it appeared that alpha-MSH was the major alpha-MSH-like immunoreactive peptide present in human blood with a level of 2-5 pg/ml. This level is similar to the one determined by direct measurements in Sep-pak pre-purified human plasma (median 2.0 pg/ml, n = 11). Des-acetyl alpha-MSH was present in human blood in only a minor quantity. We discuss this finding in view of earlier reports on alpha-MSH-like immunoreactivity in human pituitary tissue.

Characterization of the alpha-MSH-like immunoreactivity in blood and cerebrospinal fluid of the rat.

We have investigated the nature of the alpha-melanocyte stimulating hormone-like immunoreactivity (alpha-MSH-LI) in blood and cerebrospinal fluid (CSF) of the rat. Blood and CSF from intact animals were subjected to high pressure liquid chromatography (HPLC) followed by a radioimmunoassay (RIA) specific for the C-terminal part of the alpha-MSH molecule. It appeared that in both body fluids the predominant alpha-MSH-LI co-migrated with synthetic alpha-MSH and not with its des-acetyl or di-acetyl analogues. We conclude that alpha-MSH is the predominant form of alpha-MSH-LI circulating in plasma and CSF of rats from our Wistar strain.

The effect of gamma-type endorphins on alpha-MSH release in the rat.

Neuroleptic drugs increase the level of alpha-melanotropin (alpha-MSH) in the blood of the rat. We have investigated whether neuroleptic-like peptides, the gamma-type endorphins, also affect alpha-MSH release. A structure-activity study revealed that (des-enkephalin)-gamma-endorphin (DE gamma E, beta-LPH-(66-77), beta-endorphin-(6-17)) is able to increase plasma alpha-MSH levels after intracerebroventricular injection, while the longer gamma-type endorphins, i.e. gamma E (beta-LPH-(61-77)), beta-endorphin-(1-17)), and DT gamma E (beta-LPH-(62-77), beta-endorphin-(2-17)) were without effect in the dosage used. A dose-response study revealed a more or less bell-shaped relationship for the effect of DE gamma E on plasma alpha-MSH levels. The effect of DE gamma E could not be counteracted by apomorphine or naloxone. The observations indicate that DE gamma E increases plasma alpha-MSH levels in a way distinct from that of haloperidol and the opiate peptide beta-endorphin. On the other hand, a time-course of plasma alpha-MSH levels after DE gamma E administration resembled the one which has been seen after haloperidol injection. From experiments performed on pituitary neurointermediate lobes incubated in vitro, it seems not likely that DE gamma E acts directly on the dopamine receptors of the pituitary in affecting alpha-MSH release. In conclusion, it appears that DE gamma E affects alpha-MSH levels in plasma in a way distinct from that of the neuroleptic drug haloperidol and of the opiate-peptide beta-endorphin.

alpha-msh levels in cerebrospinal fluid and blood of rats during behavioral manipulations.

It was shown previously that alpha-MSH levels in peripheral blood of rats subjected to passive avoidance training did not correlate with the behavioral performance of the animals. We have investigated whether alpha-MSH levels in cerebrospinal fluid (CSF) change during passive avoidance behavior. It appeared that throughout adaptation, acquisition and retention of this avoidance behavior, alpha-MSH levels in the CSF did not change significantly. In an additional experiment in which the effects of an electric footshock versus a psychological stimulus were tested, alpha-MSH levels in CSF also remained unchanged. Since CSF alpha-MSH levels appear to be relatively stable under these behavioral conditions, it seems unlikely that the CSF functions as a direct and specific route for the afferent transport of the behaviorally active neuropeptide alpha-MSH to its sites of action in the brain. However, the psychological stimulus, which consisted of the fear of receiving an unavoidable electric footshock, did induce a significant enhancement of alpha-MSH levels in peripheral blood, suggesting that psychological stress may be involved in the release of alpha-MSH into the peripheral circulation. These results support the idea of a differentiated system of secretion of alpha-MSH into CSF and peripheral blood.

Relationships between alpha-MSH levels in blood and in cerebrospinal fluid.

Using a new cannulation technique of the cisterna magna of the rat, CSF was obtained in which alpha-MSH levels were determined under various conditions and were compared with alpha-MSH levels in plasma. Basal levels of 66 +/- 9 pg alpha-MSH/ml were found in the CSF and of 179 +/- 13 pg alpha-MSH/ml in the plasma. A rapid flow of CSF from the lateral ventricles to the cisterna magna could be established as detected by elevated alpha-MSH levels in cisternal CSF 2 min after injection of a large quantity of alpha-MSH into the ventricular system. A half-time disappearance of alpha-MSH from the CSF of 33 min was calculated. The possibility of a contribution of peripheral alpha-MSH to central melanotropic activity was suggested by the finding of elevated levels of alpha-MSH in the CSF, following artificially induced high alpha-MSH concentrations in the blood. Additionally, the movement of alpha-MSH from the CSF to the blood was demonstrated. Both these movements were shown to be independent of the pituitary gland, since hypophysectomized animals exhibited the same rate of alpha-MSH transport as intact animals.

Plasma and cerebrospinal fluid alpha-MSH levels in the rat after hypophysectomy and stimulation of pituitary alpha-MSH secretion.

Immunoreactive alpha-MSH was measured in cerebrospinal fluid (CSF) and plasma of rats. While treatment with haloperidol increased alpha-MSH levels in the plasma concentration of alpha-MSH in the CSF showed little change. Hypophysectomy also had little effect on the concentration of alpha-MSH in the CSF despite the fall in plasma alpha-MSH levels. This lack of correlation between alpha-MSH levels in the CSF and plasma suggests that the systemic circulation does not deliver alpha-MSH to the CSF. The apparently normal levels of alpha-MSH in the hypothalamus after hypophysectomy suggests that this tissue is able to synthesize alpha-MSH and it is possible that the hypothalamus is a source of the alpha-MSH in the CSF.

Involvement of ACTH and MSH in active and passive avoidance behavior.

Intracerebroventricular injection of antiserum to alpha--MSH induces a weak reduction of passive avoidance latencies after administration prior to retention testing. Administration of antiserum to ACTH 1--24 induces a more marked effect in this respect, whereas injection of a combination of these antisera results in the strongest reduction of passive avoidance retention. No effect of this treatment is observed when these antisera are injected immediately after the learning trial. In active avoidance behavior a facilitation of extinction of the response is observed after intracerebroventricular administration of the antisera prior to each extinction session. This effect is comparable with the one observed in passive avoidance behavior. From these data it is suggested that ACTH and alpha-MSH play an important role in processes related to the retrieval of information stored in the brain.